Leukotriene synthesis inhibitors

ABSTRACT

Provided are specific leukotriene synthesis inhibitor compounds and pharmaceutical compositions comprising the compounds and methods of using the compounds and the pharmaceutical compositions in treating, for example, inflammatory diseases or conditions.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit under 35 U.S.C. § of U.S.Provisional Patent Application No. 62/791,641, filed Jan. 11, 2019,which application is herein incorporated by reference in its entiretyfor all purposes.

FIELD OF THE DISCLOSURE

The present disclosure is directed to specific leukotriene synthesisinhibitor compounds and pharmaceutical compositions comprising thecompounds and methods of using the compounds and the pharmaceuticalcompositions in treating, for example, inflammatory diseases orconditions

BACKGROUND OF THE DISCLOSURE

5-Lipoxygenase (5-LO) is a key enzyme in the production of leukotrienes,proinflammatory mediators of disease. With the assistance of5-lipoxygenase activating protein (FLAP), 5-LO oxidizes substratearachidonic acid to HPETE, a transient intermediate that degrades toleukotriene A₄ (LTA₄), the immediate precursor of the biologicallyactive molecules, leukotriene C₄ (LTC₄) and leukotriene B₄ (LTB₄).Leukotriene A₄ is converted by LTA₄ hydrolase to LTB₄, or it can beconjugated with reduced glutathione by LTC4 synthase to yield LTC₄. LTC₄is converted to leukotriene D₄ (LTD₄) which undergoes conversion toleukotriene E₄ (LTE₄) by sequential amino acid hydrolysis. LeukotrienesC₄, D₄ and E₄ are collectively known as the cysteinyl leukotrienes.Leukotrienes are largely, though not exclusively, produced byleukocytes. LTB₄ is produced, for example, by neutrophils, macrophagesand mast cells. LTC₄ is produced, for example, by macrophages,eosinophils, basophils, and mast cells. Transcellular biosynthesis canalso occur. For example, LTA₄ produced in neutrophils can be deliveredto endothelial cells which lack 5-lipoxygenase but express LTC₄synthase, wherein the endothelial cells metabolize LTA₄ to LTC₄. Theamounts of LTB₄ and cysteinyl leukotrienes that various types of cellsproduce depend on the distal enzymes LTA₄ hydrolase and LTC₄ synthaserespectively. Other factors that influence leukotriene synthesis includeintracellullar localization of 5-lipoxygeanse.

Leukotrienes act by binding to specific G-protein coupled receptors thatare located on the outer plasma membrane of structural and inflammatorycells. This binding activates signalling pathways within the cellsleading to a host of biological responses present in, e.g., inflammatorydiseases and conditions. Leukotrienes have a broad array of functionalroles in disease including recruitment of leukocytes, increase in mucousrelease, increase in vascular permeability, and increased proliferation,among others.

Numerous strategies have been attempted to develop compounds that eitherinhibit the synthesis of leukotrienes or block the receptors throughwhich they exert their function. 5-LO is an important drug target fordisease indications wherein either or both of LTB₄ and the cysteinylleukotrienes are involved. 5-LO inhibitors in development can be groupedby mechanism of inhibition. Redox inhibitors reduce the active site ironof the enzyme into the inactive ferrous form. However, general redoxinhibitors interfere with multiple biological redox systems therebyleading to side effects. Another group of inhibitors are the iron ligandchelators. These compounds bind to the catalytic iron in the 5-LO enzymesuch that it is hindered from catalysing the conversion of arachidonicacid to its products. Examples of compounds within this group includeshydroxamic acid and N-hydroxyurea derivatives. Potential for sideeffects of the iron chelators render them a less favorable therapeuticoption. Non-redox competitive inhibitors offer specific inhibition ofthe 5-LO enzyme without the potential for side effects associated withthe redox and iron chelator classes. Zileuton, a compound approved forthe treatment of asthma, inhibits an estimated 26-86% of endogenousleukotriene production. Its clinical use, however, is limited by theneed to monitor hepatic enzyme levels and to administer multiple timesper day. FLAP was initially discovered as a target for MK886, and sincethen a number of compounds targeting FLAP have entered the clinic totreat respiratory and cardiovascular disease, but none have reached themarket (D. Petterson et al., Bioorg. Med. Chemm Lett. (2015), v25(13)pp. 2607-2612).

In addition, targeted inhibition of LTB₄ through blocking leukotriene A₄hydrolase (LTA₄H) has been an attractive drug target in diseases whereprimarily LTB₄ is involved. Leukotriene A₄ hydrolase (LTA₄H) is abifunctional enzyme that is pivotal in leukotriene B₄ synthesis. Theenzyme is classically known as an epoxide hydrolase activity responsiblefor generating of LTB₄ from LTA₄. It also possesses an aminopeptidaseactivity responsible for the breakdown of the tripeptides formed duringdestruction of collagen and is also chemotactic to neutrophils (A.Gaggar et al., J. Immunol (2008) v. 180(3) pp. 5662-5669; P. O'Reilly etal., J. Neuroimmunol (2009) v. 217(1-2) pp. 51-54; R. Snelgrove, Thorax(2011) v. 66(6) pp. 550-551). While LTA₄H is classically recognized forits hydrolase activity for the synthesis of pro-inflammatory LTB₄production, the aminopeptidase activity of this enzyme may play acompensatory mechanism to resolve inflammation. Therefore, a therapythat aimed at inhibiting LTB₄ production through inhibiting LTA4H mustalso maintain the aminopeptidase activity of the enzyme would beadvantageous in the treatment of inflammatory diseases.

There remains a need for leukotriene inhibitors for the treatment of,e.g., inflammatory diseases or conditions.

All of the subject matter discussed in the Background section is notnecessarily prior art and should not be assumed to be prior art merelyas a result of its discussion in the Background section. Along theselines, any recognition of problems in the prior art discussed in theBackground section or associated with such subject matter should not betreated as prior art unless expressly stated to be prior art. Instead,the discussion of any subject matter in the Background section should betreated as part of the inventor's approach to the particular problem,which in and of itself may also be inventive.

SUMMARY OF THE DISCLOSURE

In one aspect, the present disclosure provides compounds of formula (1).In another aspect, the present disclosure provides compositionscomprising a compound of formula (1), e.g., pharmaceutical compositions.In another aspect, the present disclosure provides methods of treatingvarious diseases and conditions, where the method comprisesadministering a therapeutically effective amount of a compound offormula (1) or a composition comprising a compound of formula (1).

Exemplary embodiments of the present disclosure include the compoundsset forth in Table 1, and the following embodiments which are numberedfor convenience of reference.

-   -   1) A compound of formula (1)

-   -   -   or a pharmaceutically acceptable enantiomer, diastereomer,            salt, or solvate thereof, wherein:        -   Ar is a 9- or 10-membered bicyclic aromatic ring system,            where Ar is optionally substituted with one, two or three            substituents;        -   L is selected from a direct bond and methylene;        -   R¹ is selected from hydrogen, halide, C₁-C₆alkyl,            C₁-C₆haloalkyl, C₁-C₆alkoxy, C₃-C₆cycloalkoxy, and            C₁-C₆alkoxy substituted with C₃-C₆cycloalkyl;        -   A is selected from a direct bond, —CH₂— and —CH₂CH₂—;        -   E is selected from —C(O)—R², C(OR³)R⁴R⁵ and CH(R⁶)NR⁷R⁸;        -   R² is selected from methyl, ethyl and phenyl;        -   R³ is selected from H, alkyl and substituted alkyl;        -   R⁴ is selected from hydrogen, alkyl and phenyl;        -   R⁵ is selected from C₁-C₇alkyl, C₁-C₇haloalkyl, phenyl and            substituted phenyl;        -   R⁶ is selected from hydrogen, methyl, halogenated methyl and            ethyl;        -   R⁷ is hydrogen; and        -   R⁸ is hydrogen, methyl or ethyl;        -   with the proviso that together, R⁷ and R⁸ may form a 5 or            6-membered, optionally substituted, heterocycle.

    -   2) The compound of embodiment 1 wherein Ar is an unsubstituted        9-membered bicyclic aromatic ring system.

    -   3) The compound of embodiment 1 wherein Ar is a mono-substituted        9-membered bicyclic aromatic ring.

    -   4) The compound of embodiment 1 wherein Ar is a di-substituted        9-membered bicyclic aromatic ring.

    -   5) The compound of embodiment 1 wherein Ar is a tri-substituted        9-membered bicyclic aromatic ring.

    -   6) The compound of embodiment 1 wherein Ar is an unsubstituted        10-membered bicyclic aromatic ring system.

    -   7) The compound of embodiment 1 wherein Ar is a mono-substituted        10-membered bicyclic aromatic ring.

    -   8) The compound of embodiment 1 wherein Ar is a di-substituted        10-membered bicyclic aromatic ring.

    -   9) The compound of embodiment 1 wherein Ar is a tri-substituted        10-membered bicyclic aromatic ring.

    -   10) The compound of embodiment 1 wherein Ar is selected from        1,3-benzoxazole, 2-methylquinoline, and 1,3-benzothiazole.

    -   11) The compound of embodiment 1 wherein Ar is naphthalene or a        nitrogen-substituted analog thereof selected from        1,5-naphthyridine, 1,6-naphthyridine, 1,7-naphthyridine,        1,8-naphthyridine, isoquinoline, phthalazine, 2,6-naphthyridine        and 2,7-naphthyridine.

    -   12) The compound of embodiment 1 wherein Ar is substituted with        a single —S—CH₃.

    -   13) The compound of any of embodiments 1-12 wherein L is a        direct bond.

    -   14) The compound of any of embodiments 1-12 wherein L is        methylene.

    -   15) The compound of any of embodiments 1-14 wherein R¹ is        hydrogen.

    -   16) The compound of any of embodiments 1-14 wherein R¹ is        halogen.

    -   17) The compound of any of embodiments 1-14 wherein R¹ is        C₁-C₆alkyl.

    -   18) The compound of any of embodiments 1-14 wherein R¹ is        C₁-C₆haloalkyl.

    -   19) The compound of any of embodiments 1-14 wherein R¹ is        C₁-C₆alkoxy.

    -   20) The compound of any of embodiments 1-19 wherein A is a        direct bond.

    -   21) The compound of any of embodiments 1-19 wherein A is —CH₂—.

    -   22) The compound of any of embodiments 1-19 wherein A is        —CH₂CH₂—.

    -   23) The compound of any of embodiments 1-22 wherein E is        —C(O)—R².

    -   24) The compound of any of embodiments 1-23 wherein R² is        methyl.

    -   25) The compound of any of embodiments 1-23 wherein R² is ethyl.

    -   26) The compound of any of embodiments 1-23 wherein R² is        phenyl.

    -   27) The compound of any of embodiments 1-26 wherein E is        —C(OR³)R⁴R⁵.

    -   28) The compound of any of embodiments 1-27 wherein R³ is        hydrogen.

    -   29) The compound of any of embodiments 1-28 wherein R³ is alkyl.

    -   30) The compound of any of embodiments 1-28 wherein R³ is        substituted alkyl.

    -   31) The compound of any of embodiments 1-30 wherein R⁴ is        hydrogen.

    -   32) The compound of any of embodiments 1-30 wherein R⁴ is alkyl.

    -   33) The compound of any of embodiments 1-30 wherein R⁴ is        phenyl.

    -   34) The compound of any of embodiments 1-33 wherein R⁵ is        C₁-C₇alkyl.

    -   35) The compound of any of embodiments 1-34 wherein R⁵ is        C₁-C₇haloalkyl, e.g., R⁵ is trifluoromethyl.

    -   36) The compound of any of embodiments 1-34 wherein R⁵ is        phenyl.

    -   37) The compound of any of embodiments 1-34 wherein R⁵ is        substituted phenyl.

    -   38) The compound of any of embodiments 1-37 wherein E is        —CH(R⁶)NR⁷R⁸.

    -   39) The compound of any of embodiments 1-38 wherein R⁶ is        hydrogen.

    -   40) The compound of any of embodiments 1-38 wherein R⁶ is        methyl.

    -   41) The compound of any of embodiments 1-38 wherein R⁶ is        halogenated methyl.

    -   42) The compound of any of embodiments 1-38 wherein R⁶ is ethyl.

    -   43) The compound of any of embodiments 1-38 wherein R⁸ is        hydrogen.

    -   44) The compound of any of embodiments 1-38 wherein R⁸ is        methyl.

    -   45) The compound of any of embodiments 1-38 wherein R⁸ is ethyl.

    -   46) The compound of any of embodiments 1-45 wherein R⁷ and R⁸        together form a 5 membered heterocycle.

    -   47) The compound of any of embodiments 1-45 wherein R⁷ and R⁸        together form a substituted 5 membered heterocycle.

    -   48) The compound of any of embodiments 1-45 wherein R⁷ and R⁸        together form a 6 membered heterocycle.

    -   49) The compound of any of embodiments 1-45 wherein R⁷ and R⁸        together form a substituted 6 membered heterocycle.

    -   50) The compound of embodiment 1 selected from the group        consisting of:        -   1-[4-(1,3-benzothiazol-2-yloxy)-3-methoxyphenyl]pentan-3-one;        -   1-[4-(1,3-benzoxazol-2-yloxy)-3-methoxyphenyl]pentan-3-one;        -   1-[4-(1,3-benzothiazol-2-yloxy)-3-methoxyphenyl]-3-(trifluoromethyl)pentan-3-ol;        -   1-{3-methoxy-4-[(4-methylsulfanyl-1,3-benzothiazol-2-yl)oxy]phenyl}-3-(trifluoromethyl)pentan-3-ol;        -   1-[4-(1-methyl-1H-benzimidazol-2-yloxy)-3-methoxyphenyl]-3-(trifluoromethyl)pentan-3-ol;        -   1-{3-methoxy-4-[(6-methylsulfonyl-1,3-benzothiazol-2-yl)oxy]phenyl}-3-(trifluoromethyl)pentan-3-ol;        -   1-{4-[(4,6-difluoro-1,3-benzothiazol-2-yl)oxy]-3-methoxyphenyl}-3-(trifluoromethyl)pentan-3-ol;        -   1-{4-[(6-fluoro-1,3-benzothiazol-2-yl)oxy]-3-methoxyphenyl}-3-(trifluoromethyl)pentan-3-ol;        -   1-{4-[(6-methoxy-1,3-benzothiazol-2-yl)oxy]-3-methoxyphenyl}-3-(trifluoromethyl)pentan-3-ol;        -   4-[4-(1,3-benzothiazol-2-yloxy)-3-methoxyphenyl]butan-2-one;        -   4-[4-(1,3-benzothiazol-2-yloxy)-3-methoxyphenyl]-1,1,1-trifluoro-2-methylbutan-2-ol;        -   1-[4-(1,3-benzothiazol-2-yloxy)-3-(iso-propyloxy)-phenyl]pentan-3-one;        -   1-[4-(1,3-benzothiazol-2-yloxy)-3-(cyclopentyloxy)-phenyl]pentan-3-one;        -   1-[4-(1,3-benzothiazol-2-yloxy)-3-(cyclopropyl-methoxy)-phenyl]pentan-3-one;        -   1-[4-(1,3-benzothiazol-2-yloxy)-3-(iso-propyloxy)phenyl]-3-(trifluoromethyl)pentan-3-ol        -   1-[4-(1,3-benzothiazol-2-yloxy)-3-(cyclopentyloxy)-phenyl]-3-(trifluoromethyl)-pentan-3-ol;        -   1-[4-(1,3-benzothiazol-2-yloxy)-3-(cyclopropyl-methoxy)-phenyl]-3-(trifluoromethyl)-pentan-3-ol;        -   4-(3-methoxy-4-{[4-(methylsulfanyl)-1,3-benzothiazol-2-yl]oxy}phenyl)butan-2-one;        -   1,1,1-trifluoro-4-(3-methoxy-4-{[4-(methylsulfanyl)-1,3-benzothiazol-2-yl]oxy}phenyl)-2-methylbutan-2-ol;        -   1-[4-(1,3-benzothiazol-2-yloxy)-3-ethoxyphenyl]-pentan-3-one;        -   1-[4-(1,3-benzothiazol-2-yloxy)-3-ethoxyphenyl]-3-(trifluoromethyl)pentan-3-ol;        -   4-[4-(1,3-benzothiazol-2-yloxy)-3-methoxyphenyl]-butan-2-ol;        -   4-[4-(1,3-benzothiazol-2-yloxy)-3-methoxyphenyl]-2-(phenyl)butan-2-ol;        -   4-[4-(1,3-benzothiazol-2-yloxy)-3-methoxyphenyl]-2-methylbutan-2-ol;        -   4-[4-(1,3-benzoxazol-2-yloxy)-3-methoxyphenyl]butan-2-one;        -   4-[4-(1,3-benzoxazol-2-yloxy)-3-methoxyphenyl]-2-methylbutan-2-ol;        -   1-[4-(1,3-benzoxazol-2-yloxy)-3-methoxyphenyl]-3-methylpentan-3-ol;        -   4-[4-(1,3-benzoxazol-2-yloxy)-3-methoxyphenyl]-2-phenylbutan-2-ol;        -   3-[4-(1,3-benzothiazol-2-yloxy)-3-ethoxyphenyl]-1-phenylpropan-1-one;        -   4-[3-ethoxy-4-(1,3-benzothiazol-2-yloxy)phenyl]-1,1,1-trifluoro-2-phenylbutan-2-ol;        -   3-[4-(1,3-benzothiazol-2-yloxy)-3-methoxyphenyl]-1-phenylpropan-1-one;        -   3-[4-(1,3-benzothiazol-2-yloxy)-3-methoxyphenyl]-1-phenylpropan-1-ol;        -   3-[4-(1,3-benzothiazol-2-yloxy)-3-methoxyphenyl]-1-(trifluoromethyl)-1-phenylpropan-1-ol;        -   2-{2-methoxyl-4-[3-phenyl-3-(pyrrolidin-1-yl)propyl]phenoxyl-1,3-benzothiazole;        -   1-[4-(1,3-benzothiazol-2-yloxy)-3-methoxyphenyl]pentan-3-amine;        -   4-{1-[3-methoxy-4-(1,3-benzothiazol-2-yloxy)phenyl]pentan-3-yl}morpholine;        -   1-[4-(1,3-benzothiazol-2-yloxy)-3-methoxyphenyl]-2,2,2-trifluoroethanol;        -   1-[4-(1,3-benzothiazol-2-yloxy)-3-methoxyphenyl]-N-ethyl-2,2,2-trifluoroethanamine;        -   2,2,2-trifluoro-1-(3-methoxy-4-{[4-(methylsulfanyl)-1,3-benzothiazol-2-yl]oxy}phenyl)ethanol;        -   4-[4-(1,3-benzothiazol-2-yloxy)phenyl]-1,1,1-trifluoro-2-methylbutan-2-ol;        -   4-[4-(1,3-benzothiazol-2-yloxy)phenyl]butan-2-ol;        -   1-[4-(1,3-benzothiazol-2-yloxy)phenyl]-3,4-dimethylpentan-3-ol;        -   1-[4-(1,3-benzothiazol-2-yloxy)phenyl]-3-methylpentan-3-ol;        -   4-[4-(1,3-benzothiazol-2-yloxy)phenyl]-2-phenylbutan-2-ol;        -   4-[4-(1,3-benzothiazol-2-yloxy)phenyl]-2-(4-fluorophenyl)butan-2-ol;        -   1-[4-(1,3-benzoxazol-2-yloxy)phenyl]-3-methylpentan-3-ol;        -   4-[4-(1,3-benzoxazol-2-yloxy)phenyl]-2-phenylbutan-2-ol;        -   1-[4-(1,3-benzothiazol-2-yloxy)phenyl]pentan-3-one;        -   1-[4-(1,3-benzothiazol-2-yloxy)-3-chlorophenyl]pentan-3-one;        -   1-[4-(1,3-benzothiazol-2-yloxy)phenyl]-3-(trifluoromethyl)pentan-3-ol;        -   1-[4-(1,3-benzothiazol-2-yloxy)-3-chlorophenyl]-3-(trifluoromethyl)pentan-3-ol;        -   1-[4-(1,3-benzothiazol-2-yloxy)-3-fluorophenyl]-pentan-3-one;        -   1-[4-(1,3-benzothiazol-2-yloxy)-3-(trifluoromethyl)-phenyl]pentan-3-one;        -   1-[4-(1,3-benzothiazol-2-yloxy)-3-fluorophenyl]-3-(trifluoromethyl)pentan-3-ol;        -   1-[4-(1,3-benzothiazol-2-yloxy)-3-(trifluoromethyl)-phenyl]-3-(trifluoromethyl)-pentan-3-ol;        -   2-{4-[3-(pyrrolidin-1-yl)butyl]phenoxy}-1,3-benzothiazole;        -   1-{4-[4-(1,3-benzothiazol-2-yloxy)phenyl]butan-2-yl}pyrrolidine-2-carboxylic            acid;        -   2-{4-[3-(pyrrolidin-1-yl)pentyl]phenoxy}-1,3-benzothiazole;        -   1-[4-(1,3-benzothiazol-2-yloxy)phenyl]ethanone;        -   1-[4-(1,3-benzothiazol-2-yloxy)phenyl]ethanol;        -   2-[4-(1,3-benzothiazol-2-yloxy)phenyl]butan-2-ol;        -   2-{4-[1-(pyrrolidin-1-yl)ethyl]phenoxy}-1,3-benzothiazole;        -   2-[4-(1,3-benzothiazol-2-yloxy)phenyl]-1,1,1-trifluoropropan-2-ol;        -   2-[4-(pyrrolidin-1-ylmethyl)phenoxy]-1,3-benzothiazole;        -   1-[4-(1,3-benzothiazol-2-yloxy)benzyl]pyrrolidine-2-carboxylic            acid;        -   1-[4-(1,3-benzothiazol-2-yloxy)phenyl]-2,2,2-trifluoroethanol;        -   1-[4-(1,3-benzothiazol-2-yloxy)-3-chlorophenyl]-2,2,2-trifluoroethanol;        -   1-[4-(1,3-benzothiazol-2-yloxy)phenyl]-N-ethyl-2,2,2-trifluoroethanamine;        -   1-{4-[(2-methyl-1,3-benzothiazol-6-yl)oxy]phenyl}ethanone;        -   1,1,1-trifluoro-2-{4-[(2-methyl-1,3-benzothiazol-6-yl)oxy]phenyl}propan-2-ol;        -   1-{4-[(2-methyl-1,3-benzothiazol-6-yl)oxy]phenyl}ethanol;        -   1-[4-(1,3-benzothiazol-2-yloxy)-3-methoxyphenyl]-ethanone;        -   2-[4-(1,3-benzothiazol-2-yloxy)-3-methoxyphenyl]-1,1,1-trifluoropropan-2-ol;        -   4-[4-(1,3-benzothiazol-2-yloxy)-3-chlorophenyl]butan-2-one;        -   4-[4-(1,3-benzothiazol-2-yloxy)-3-chlorophenyl]-1,1,1-trifluoro-2-methylbutan-2-ol;        -   1-(4-{[4-(methylsulfanyl)-1,3-benzothiazol-2-yl]oxy}phenyl)ethanol;        -   2-[4-(1,3-benzothiazol-2-yloxy)phenyl]propan-2-ol;        -   1-[4-(1,3-benzothiazol-2-yloxy)phenyl]-2,2,2-trifluoro-N-methylethanamine;        -   1-{4-[(4,6-difluoro-1,3-benzothiazol-2-yl)oxy]phenyl}-2,2,2-trifluoroethanol;        -   1-{4-[(4,6-difluoro-1,3-benzothiazol-2-yl)oxy]phenyl}ethanol;        -   2-{4-[(4,6-difluoro-1,3-benzothiazol-2-yl)oxy]phenyl}-1,1,1-trifluoropropan-2-ol;        -   1-{4-[(1,3-benzothiazol-2-yl}oxy]-2-methoxyphenyl}-2,2,2-trifluoroethan-1-ol;        -   1,1,1-trifluoro-2-methyl-4-[4-(quinolin-2-ylmethoxy)phenyl]butan-2-ol;        -   1,1,1-trifluoro-4-[3-methoxy-4-(quinolin-2-ylmethoxy)phenyl]-2-methylbutan-2-ol;        -   1-[4-(quinolin-2-ylmethoxy)-phenyl]-3-(trifluoromethyl)-pentan-3-ol;        -   1-[4-(1,3-benzothiazol-2-yloxy)-3-(cyclopentyloxy)-phenyl]pentan-3-ol;        -   1-[4-(1,3-benzothiazol-2-yloxy)-3-(cyclopropylmethoxy)-phenyl]-pentan-3-ol;        -   1-[4-(1,3-benzothiazol-2-yloxy)-3-methoxyphenyl]-3-(4-methylpiperazinyl-1yl)pentane;        -   4-{4-[(quinolinyl-2-yl)methoxy]phenyl}butan-2-one;        -   4-{4-[(quinoline-2-yl)methoxy]phenyl}butan-2-pyrrolidine;        -   1-(3-methoxy-4-{[4-(methylsulfanyl)-1,3-benzothiazol-2-yl]oxy}phenyl)pentan-3-methyl-3-ol;        -   1-(3-methoxy-4-{[4-(methylsulfanyl)-1,3-benzothiazol-2-yl]oxy}phenyl)pentan-3-one;        -   1-(3-methoxy-4-{[4-(methylsulfanyl)-1,3-benzothiazol-2-yl]oxy}phenyl)pentan-3-ol;        -   1-(4-{[4-(methylsulfanyl)-1,3-benzothiazol-2-yl]oxy}phenyl)pentan-3-one;        -   1-(4-{[4-(methylsulfanyl)-1,3-benzothiazol-2-yl]oxy}phenyl)-3-(trifluoromethyl)pentan-3-ol;        -   1-[4-(1,3-benzothiazol-2-yloxy)-3-methoxyphenyl]pentan-3-ol;        -   1,1,1-trifluoro-2-[4-(quinolin-2-ylmethoxy)phenyl]propan-2-ol;        -   1,1,1-trifluoro-2-[3-methoxy-4-(quinolin-2-ylmethoxy)phenyl]butan-3-ol;            and        -   1,1,1-trifluoro-2-[3-methoxy-4-(quinolin-2-ylmethoxy)phenyl]propan-2-ol.

    -   51) The compound of embodiment 1 as a racemic mixture of        enantiomers of compounds of formula (1).

    -   52) The compound of any of embodiments 1-51 as a non-racemic        mixture of enantiomers of compounds of formula (1).

    -   53) The compound of any of embodiments 1-51 as an isolated (S)        enantiomer.

    -   54) The compound of any of embodiments 1-51 as an isolated (R)        enantiomer.

    -   55) The compound of embodiment 1 wherein:        -   Ar is a 9- or 10-membered bicyclic ring system comprising            two aromatic rings, where Ar is unsubstituted or is            substituted with one substituent selected from halide,            C₁₋₆alkyl; —S—C₁₋₆alkyl; —O—C₁₋₆alkyl; and —SO₂—C₁₋₆alkyl;        -   L is selected from a direct bond and —CH₂— (methylene);        -   R¹ is selected from hydrogen, halide, C₁-C₆alkyl,            C₁-C₆haloalkyl, C₁-C₆alkoxy, C₃-C₆cycloalkoxy and            C₁-C₆alkoxy substituted with C₃-C₆cycloalkyl;        -   A is selected from a direct bond, —CH₂— and —CH₂CH₂—;        -   E is selected from —C(O)—R², C(OR³)R⁴R⁵ and CH(R⁶)NR⁷R³;        -   R² is selected from methyl, ethyl and phenyl;        -   R³ is H;        -   R⁴ is selected from hydrogen, C₁-C₇alkyl and phenyl;        -   R⁵ is selected from C₁-C₇alkyl, C₁-C₇haloalkyl, phenyl and            halophenyl;        -   R⁶ is selected from hydrogen, methyl, halogenated methyl and            ethyl; and        -   R⁷ is hydrogen and R⁸ is hydrogen, methyl or ethyl; or R⁷            and R⁸ together form a 5- or 6-membered heterocycle which is            optionally substituted with a substituent selected from            C₁-C₆alkyl and carboxylic acid.

    -   56) The compound of embodiment 55 wherein Ar is        1,3-benzothiazole.

    -   57) The compound of embodiment 55 wherein Ar is selected from        1,3-benzoxazole and quinoline.

    -   58) The compound of embodiment 55 wherein Ar is substituted with        a single substituent which is —S—CH₃.

    -   59) The compound of any of embodiments 55-58 wherein L is a        direct bond.

    -   60) The compound of any of embodiments 55-58 wherein L is        methylene.

    -   61) The compound of any of embodiments 55-60 wherein R¹ is        hydrogen or C₁-C₆alkoxy.

    -   62) The compound of any of embodiments 55-61 wherein A is a        direct bond.

    -   63) The compound of any of embodiments 55-61 wherein A is        —CH₂CH₂—.

    -   64) The compound of any of embodiments 55-63 wherein E is        —C(OR³)R⁴R⁵.

    -   65) The compound of any of embodiments 55-64 as a non-racemic        mixture of enantiomers of compounds of formula (1).

    -   66) The compound of embodiment 55 selected from the group        consisting of:        -   1-[4-(1,3-benzothiazol-2-yloxy)-3-methoxyphenyl]-3-(trifluoromethyl)pentan-3-ol;        -   1-{3-methoxy-4-[(4-methylsulfanyl-1,3-benzothiazol-2-yl)oxy]phenyl}-3-(trifluoromethyl)pentan-3-ol;        -   1-{4-[(4,6-difluoro-1,3-benzothiazol-2-yl)oxy]-3-methoxyphenyl}-3-(trifluoromethyl)pentan-3-ol;        -   1-{4-[(6-fluoro-1,3-benzothiazol-2-yl)oxy]-3-methoxyphenyl}-3-(trifluoromethyl)pentan-3-ol;        -   4-[4-(1,3-benzothiazol-2-yloxy)-3-methoxyphenyl]-1,1,1-trifluoro-2-methylbutan-2-ol;        -   1,1,1-trifluoro-4-(3-methoxy-4-{[4-(methylsulfanyl)-1,3-benzothiazol-2-yl]oxy}phenyl)-2-methylbutan-2-ol;        -   1,1,1-trifluoro-2-{4-[(2-methyl-1,3-benzothiazol-6-yl)oxy]phenyl}propan-2-ol;        -   1,1,1-trifluoro-2-methyl-4-[4-(quinolin-2-ylmethoxy)phenyl]butan-2-ol;        -   1,1,1-trifluoro-4-[3-methoxy-4-(quinolin-2-ylmethoxy)phenyl]-2-methylbutan-2-ol;        -   1-[4-(quinolin-2-ylmethoxy)-phenyl]-3-(trifluoromethyl)-pentan-3-ol;        -   1-(3-methoxy-4-{[4-(methylsulfanyl)-1,3-benzothiazol-2-yl]oxy}phenyl)pentan-3-ol;            and        -   1-(4-{[4-(methylsulfanyl)-1,3-benzothiazol-2-yl]oxy}phenyl)-3-(trifluoromethyl)pentan-3-ol.

    -   67) A pharmaceutical composition comprising a compound of any of        embodiments 1-66, or a pharmaceutically acceptable enantiomer,        salt or solvate thereof, and at least one pharmaceutically        acceptable carrier, diluent, excipient and/or adjuvant.

    -   68) The pharmaceutical composition of embodiment 67 in the form        of an eyedrop.

    -   69) A method of treating an inflammatory disease or inflammatory        condition comprising administrating to a subject in need thereof        an effective amount of a compound of any of embodiments 1-66 or        a composition of embodiment 67.

    -   70) The method of embodiment 69 for treating an ocular        inflammatory disease or an ocular inflammatory condition.

    -   71) A method of treating a respiratory disease or condition        comprising administering to a subject in need thereof a        therapeutically-effective amount of a compound of any of        embodiments 1-66 or a composition of embodiment 67.

    -   72) A method of treating a neurodegenerative disease, condition        or disorder comprising administering to a subject in need        thereof a therapeutically-effective amount of a compound of any        of embodiments 1-66 or a composition of embodiment 67.

    -   73) A method of treating respiratory disease, lung dysfunction        or lung conditions, such as asthma, chronic obstructive        pulmonary disease (COPD), cystic fibrosis, bronchopulmonary        dysplasia and Idiopathic pulmonary fibrosis (IPF), comprising        administrating to a subject in need thereof an effective amount        of a compound of any of embodiments 1-66 or a composition of        embodiment 67.

    -   74) A method of treating an autoimmune disease or autoimmune        condition such as arthritis, Otis, and multiple sclerosis,        comprising administrating to a subject in need thereof an        effective amount of a compound of any of any of embodiments 1-66        or a composition of embodiment 67.

    -   75) A method of treating an allergic disease comprising        administrating to a subject in need thereof an effective amount        of a compound of any of any of embodiments 1-66 or a composition        of embodiment 67.

    -   76) A method of treating a conjunctivitis comprising        administrating to a subject in need thereof an effective amount        of a compound of any of any of embodiments 1-66 or a composition        of embodiment 67.

    -   77) A method of treating uveitis comprising administrating to a        subject in need thereof an effective amount of a compound of any        of any of embodiments 1-66 or a composition of embodiment 67.

    -   78) A method of treating dry eye comprising administrating to a        subject in need thereof an effective amount of a compound of any        of any of embodiments 1-66 or a composition of embodiment 67.

    -   79) A method of treating diabetic retinopathy comprising        administering to a subject in need thereof a        therapeutically-effective amount of a compound of any of any of        embodiments 1-66 or a composition of embodiment 67.

    -   80) A method of treating age-related macular degeneration        comprising administering to a subject in need thereof a        therapeutically-effective amount of a compound of any of any of        embodiments 1-66 or a composition of embodiment 67.

    -   81) A method of treating diabetic macular edema comprising        administering to a subject in need thereof a        therapeutically-effective amount of a compound of any of any of        embodiments 1-66 or a composition of embodiment 67.

    -   82) A method of treating skin disorders or skin conditions, such        as atopic dermatitis, psoriasis, and acne vulgaris comprising        administrating to a subject in need thereof an effective amount        of a compound of any of any of embodiments 1-66 or a composition        of embodiment 67.

    -   83) A method of treating cancer comprising administrating to a        subject in need thereof an effective amount of a compound of any        of any of embodiments 1-66 or a composition of embodiment 67.

    -   84) A method of treating a neuroinflammatory disease or        neurodegenerative disease, such as Alzheimer's disease,        comprising administrating to a subject in need thereof an        effective amount of a compound of any of any of embodiments 1-66        or a composition of embodiment 67.

    -   85) A method of treating Sjogren-Larsson-Syndrome comprising        administrating to a subject in need thereof an effective amount        of a compound of any of any of embodiments 1-66 or a composition        of embodiment 67.

    -   86) A method of treating cardiovascular (CV) disease comprising        administrating to a subject in need thereof an effective amount        of a compound of any of any of embodiments 1-66 or a composition        of embodiment 67.

Any two or more of the embodiments disclosed herein may be combined inorder to describe compounds, compositions and methods of the presentdisclosure.

This Brief Summary has been provided to introduce certain concepts in asimplified form that are further described in detail below in theDetailed Description. Except where otherwise expressly stated, thisBrief Summary is not intended to identify key or essential features ofthe claimed subject matter, nor is it intended to limit the scope of theclaimed subject matter.

The details of one or more embodiments are set forth in the descriptionbelow. The features illustrated or described in connection with oneexemplary embodiment may be combined with the features of otherembodiments. Thus, any of the various embodiments described herein canbe combined to provide further embodiments. Aspects of the embodimentscan be modified, if necessary to employ concepts of the various patents,applications and publications as identified herein to provide yetfurther embodiments. Other features, objects and advantages will beapparent from the description, the drawings, and the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the effect of Compound 104 on LPS-induced neutrophilinfiltration into the lung. Animals were treated orally with 10 mg/kg ofCompound 104, 1 mg/kg Dexamethasone or dosing vehicle 1 hr before and 2hrs after 2.5 mg/kg LPS was administered intratracheally. Animals wereeuthanized 6 hr post-LPS and the BAL was collected from the lung. Valuesrepresent the mean±standard deviation, n=7-10 animals per group.

FIG. 2 shows the effect of Compound 104 on clinical scores in the EIUrat model. Animals were treated with 30 mg/kg of Compound 104 or dosingvehicle orally 15 min before and 5 hrs after 75 μg of LPS fromSalmonella Typhimurium in saline 2.5 mg/kg LPS was administeredsubcutaneously in the hind foot pad of each foot. Mean clinical scoreswere determined at 24 hrs post LPS dose. Values represent themean±standard deviation, n=3 per group.

FIG. 3. shows the superior ability of Compound 104 to distribute to theposterior section (vitreous+retina) of the eye compared to standard ofcare Prednisolone. Sprague Dawley rats received a 10 μL drop of eitherCompound 104 (0.4%) or commercially available ophthalmic prednisoloneacetate (1%) and tissues were removed 2 hours post administration tomeasure compound concentration. The resulting data in FIG. 3, whichrepresent the mean±standard deviation, n=5 eyes per drug, shows thatCompound 104 was absorbed into the posterior segment at levelsapproximately 50 times that of prednisolone 2 hours afteradministration.

FIG. 4A shows the effect of Compound 104 on clinical scores andhistological evaluation in the EAU rat model. Animals were immunizedwith 30 μg of peptide in an emulsion containing 2 mg/mL Complete FreundsAdjuvant on day 0. From day 6 post immunization, animals received 10 μLof 0.5% wt/vol Compound 104 or vehicle topically in each eye every 3hours for four doses each day, and once orally (30 mg/kg) immediatelyafter the last topical dose each day. Animals were treated daily untileuthanized 10 days post-immunization and tissues collected forhistological examination. Values represent the mean±standard deviationof 4 eyes, n=2 per group. In this Figure, 4A the mean clinical scoreswere determined at various times post immunization as indicated.

FIG. 4B is data taken from the same experiment as described for FIG. 4A,where FIG. 4B shows histological scores that were obtained 10 days postimmunization.

FIG. 4C is data taken from the same experiments as described for FIG.4A, where FIG. 4C shows retinal thickness measurements that weredetermined from histological slides 10 days post immunization.

DETAILED DESCRIPTION

The present invention may be understood more readily by reference to thefollowing detailed description of the preferred embodiments of theinvention and the Examples included herein. Before describing theinvention in further detail, certain definitions as used herein areprovided with the following definitions, and certain conventions usedherein are also set forth.

The terms used herein should be understood to have their ordinarymeaning to the person of ordinary skill in the art of organic chemicals.That notwithstanding, and except where otherwise stated, the followingdefinitions apply through the specification and claims. Thesedefinitions apply regardless of whether a term is used by itself or isinstead used as part of a larger name. For example, the definition of“alkyl” applies to the term “alkyl” used by itself as well as the“alkyl” portion of words that incorporate the alkyl concept, e.g.,“hydroxyalkyl”, “haloalkyl”, “O-alkyl”, etc.

Chemical names, common names, and chemical structures may be usedinterchangeably to describe the same compound. For example, thecompounds of formula (1) may be referred to herein by chemical structureand/or by chemical name. In an instance where both the structure and thename of a compound are provided and there is a discrepancy between thename and the structure, then it is to be understood that the structuralrepresentation of the compound controls.

As discussed further herein, the term “substituted” means that one ormore hydrogens on a designated or selected atom is replaced with aselection from an indicated group, provided that the designated atom'snormal valency under the existing circumstances is not exceeded, andthat the substitution results in a stable compound. Combinations ofsubstituents and/or variables are permissible only if such combinationsresult in stable compounds. By “stable compound” or “stable structure”it is meant that a compound is sufficiently robust to survive isolationto a useful degree of purity from a reaction mixture, and formulationinto an efficacious therapeutic composition. It should also be notedthat any carbon as well as heteroatom with unsatisfied valences in thetext, schemes, examples and tables herein is assumed to have thesufficient number of hydrogen atom(s) to satisfy the atom's normalvalence.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to the specified number of carbon atoms,and which is attached to the rest of the molecule by a single bond,e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl,n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, andthe like. In one embodiment the alkyl group has 1 carbon. In oneembodiment the alkyl group has 2 carbons. In one embodiment the alkylgroup has 3 carbons. In one embodiment the alkyl group has 4 carbons. Inone embodiment the alkyl group has 4 carbons. In one embodiment thealkyl group has 5 carbons. In one embodiment the alkyl group has 6carbons. Two or more of these embodiments may be combined to describecompounds of the disclosure. “Alkoxy” refers to —O-alkyl. “Cycloalkyl”refers to a cyclic aliphatic radical having no unsaturation such ascyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. “Cycloalkoxy”refers to —O— cycloalkyl.

“Aryl” refers to a hydrocarbon ring system radical comprising hydrogen,6 to 18 carbon atoms and at least one aromatic ring. In one embodimentthe aryl ring system has 6 to 12 carbon atoms. In one embodiment thearyl ring system has 6 to 10 carbon atoms. For purposes of thisdisclosure, the aryl radical may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused or bridged ringsystems. Aryl radicals include, but are not limited to, aryl radicalsderived from aceanthrylene, acenaphthylene, acephenanthrylene,anthracene, azulene, benzene, chrysene, fluoranthene, fluorene,as-indacene, s-indacene, indane, indene, naphthalene, phenalene,phenanthrene, pleiadene, pyrene, and triphenylene. Unless statedotherwise specifically in the specification, an aryl group may beoptionally substituted by one or more substituents independentlyselected at each occurrence.

“Compounds of the present disclosure” (unless specifically identifiedotherwise) and the equivalent term “compounds of the (or this)invention” (unless specifically identified otherwise) refer to compoundsof Formula (1), including subsets thereof, and all pure and mixedstereoisomers (including diastereoisomers and enantiomers), tautomersand isotopically labeled compounds. Hydrates and solvates of thecompounds of this invention/disclosure are also considered within thescope of the term compounds of this invention/disclosure. The compoundsmay exist in one or more crystalline states, i.e., as co-crystals orpolymorphs, or they may exist as amorphous solids, or they may exist asoils. All such forms are encompassed by the invention and the claims.Compounds of “Formula (1)”, “Formula 1”, “formula (1)”, “formula 1” andthe like may be used interchangeably herein and no difference ordistinction is meant.

“Effective amount,” “therapeutic amount,” “therapeutically effectiveamount,” or “effective dose” refers to an amount or dose of the activecompound as described herein sufficient to elicit a desiredpharmacological or therapeutic effect in a subject. In the case ofcompounds to treat inflammation, an effective amount will be ananti-inflammatory amount. In this context, “effective amounts,”“therapeutic amounts,” “therapeutically effective amount,” and“effective doses” can be readily determined by ordinarily skilledartisans following the teachings of this disclosure and employing toolsand methods generally known in the art, often based on routine clinicalor patient-specific factors. It will be understood, however, that theattending physician, within the scope of sound medical judgment, willdecide the total daily dosage of the compound. The specifictherapeutically effective dose level for any particular patient willdepend upon a variety of factors including the disorder being treatedand the severity of the disorder; the desired result to be obtained, theactivity of the specific compound employed; the specific compositionemployed; the age, body weight, general health, gender and diet of thepatient; the time of administration, route of administration, and rateof excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or coincidental with the specificcompound employed; and like factors well known in the medical arts. As ageneral guideline however, the total daily dose will typically rangefrom about 0.0001 mg/kg/day to about 100 mg/kg/day in single or individed doses. Typically, dosages for humans will range from about 0.1mg to about 4000 mg per day, in a single or multiple doses

“Fused” refers to any ring system described herein which is fused to anexisting ring structure in the compounds of the disclosure. When thefused ring system is a heterocyclyl or a heteroaryl, any carbon in theexisting ring structure which becomes part of the fused ring system maybe replaced with a nitrogen.

“Halo” refers to chloro, bromo, fluoro, and iodo. The term “halogen”refers to fluorine (which may be depicted as —F), chlorine (which may bedepicted as —Cl), bromine (which may be depicted as —Br), or iodine(which may be depicted as —I). In one embodiment, the halogen ischlorine. In another embodiment, the halogen is fluorine. In anotherembodiment, the halogen is bromine. Thus, halophenyl refers to a phenylgroup having at least one halogen substituent which replaces a hydrogennormally present on phenyl. Halogenated CH₂ refers to a CH₂ group thathas at least one halogen substitution in place of hydrogen, e.g., CHFand CF₂.

“Haloalkyl” refers to an alkyl group having at least one halogensubstitution in lieu of a C—H bond. In one embodiment, there is a singlehalogen substituent on the named group (e.g., phenyl, alkyl). Inembodiments, there are two halogen substituents, or 1-2 halogensubstituents, or three halogen substituents, or 1-3 halogensubstituents, where as mentioned previously, the halogen may befluorine, or selected from fluorine and chlorine. A subset of haloalkylis “fluoroalkyl”, which refers to alkyl groups that are substituted byone or more fluorine atoms, up to the total number of hydrogen atomspresent on the alkyl moiety. Thus, C₁-C₆fluoroalkyl refers tofluorinated alkyl groups, e.g., trifluoromethyl or difluoroethyl (i.e.,CF₃ and CH₂CHF₂). As used herein, “C₁-C₆fluoroalkyl” denotes astraight-chain or branched alkyl group containing from 1 to 6, e.g., 1,2, 3, or 4 carbon atoms. Examples of suitable C₁-C₆fluoroalkyl radicalsare methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl,tert-butyl, where the radical contains 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10or more fluorine substituents, for example, the radical may contain 1, 2or 3 fluorine substituents.

“Heteroaryl” refers to “aryl” as defined herein, wherein the aromaticring includes one or more heteroatoms, preferably selected from N, O andS. Thus, a heteroaryl radical refers to an aromatic ring system radicalwherein the ring atoms are selected from carbon, nitrogen, oxygen andsulfur, and include at least one of nitrogen, oxygen and sulfur. Forpurposes of this disclosure, the heteroaryl radical may be a monocyclic,bicyclic, tricyclic or tetracyclic ring system, which may include fusedor bridged ring systems. Optionally, the heteroaryl radical is a 5-, 6-or 7-membered heteroaryl group. When there are multiple O and S atoms inthe heteroaryl ring system, the O atoms and/or S atoms are preferablynot linked directly to one another. Exemplary heteroaryl groups include5-membered rings, such as pyrrole, pyrazole, imidazole, 1,2,3-triazole,1,2,4-triazole, tetrazole, furan, thiophene, selenophene, oxazole,isoxazole, 1,2-thiazole, 1,3-thiazole, 1,2,3-oxadiazole,1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole,1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole. The heteroarylgroup may be a 6-membered ring, such as pyridine, pyridazine,pyrimidine, pyrazine, 1,3,5-triazine, 1,2,4-triazine, 1,2,3-triazine,1,2,4,5-tetrazine, 1,2,3,4-tetrazine, 1,2,3,5-tetrazine, or fused ringsincluding a 6-membered ring such as indole, isoindole, indolizine,indazole, benzimidazole, benzotriazole, purine, naphthimidazole,phenanthrimidazole, pyridimidazole, pyrazinimidazole,quinoxalinimidazole, benzoxazole, naphthoxazole, anthroxazole,phenanthroxazole, isoxazole, benzothiazole, benzofuran, isobenzofuran,dibenzofuran, quinoline, isoquinoline, pteridine, benzo-5,6-quinoline,benzo-6,7-quinoline, benzo-7,8-quinoline, benzoisoquinoline, acridine,phenothiazine, phenoxazine, benzopyridazine, benzopyrimidine,quinoxaline, phenazine, naphthyridine, azacarbazole, benzocarboline,phenanthridine, phenanthroline, thieno[2,3b]thiophene,thieno[3,2b]thiophene, dithienothiophene, isobenzothiophene,dibenzothiophene, and benzothiadiazo-thiophene. Unless stated otherwisespecifically in the specification, the ring atoms of a heteroaryl groupmay be optionally substituted by one or more substituents independentlyselected at each ring atom.

“Hydroxyalkyl” refers to an alkyl group having at least one hydroxyl(—OH; also called hydroxy) substitution in lieu of a C—H bond. In oneembodiment, there is a single hydroxyl substituent on the named group(e.g., phenyl, alkyl). In embodiments, there are two hydroxylsubstituents, or 1-2 hydroxyl substituents, or three hydroxylsubstituents, or 1-3 hydroxyl substituents. As used herein, “C₁-C₆hydroxyalkyl” denotes a straight-chain or branched alkyl groupcontaining from 1 to 6, e.g., 1, 2, 3, 4, 5 or 6 carbon atoms. Examplesof suitable C₁-C₆hydroxyalkyl radicals are methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, where the radicalcontains 1 or more hydroxyl substituents, for example, as in oneembodiment, the radical may contain 1 hydroxyl substituent.

“Independently selected” in reference to a group of options, e.g., agroup of substituents, indicates that each substituent is selectedwithout regard to the selection that is made for any other substituent,i.e., each substituent is independently selected. Thus, each selectedsubstituent may be identical to or different from the othersubstituent(s) selected from a group of substituents. For additionalclarity, it will be explained that a disclosure that something isselected from a group means that the selection is independently done ateach occurrence in the event that the selection is done multiple times.Unless otherwise explicitly stated, and regardless of whether theselection is explicitly stated to be made independently, selections ofatoms and/or substituents are independently selected.

“Mammal” refers to human or animals including livestock and companionanimals. The phrase “companion animal” or “companion animals” refers toanimals kept as pets, e.g., cats, dogs, and horses. The term “livestock”refers to animals reared or raised in an agricultural setting to makeproducts such as food or fiber, or for its labor, e.g., cattle, goats,horses, pigs, sheep, lambs, and rabbits, as well as birds, such aschickens, ducks and turkeys.

“Pharmaceutically acceptable” refers to being suitable for use inmammals, companion animals or livestock animals. Thus, apharmaceutically acceptable substance or composition must be compatiblechemically and/or toxicologically, with the other ingredients comprisinga formulation, and/or the mammal being treated therewith.

“Pharmaceutically acceptable carrier, diluent or excipient” includeswithout limitation any adjuvant, carrier, excipient, glidant, sweeteningagent, diluent, preservative, dye/colorant, flavor enhancer, surfactant,wetting agent, dispersing agent, suspending agent, stabilizer, isotonicagent, solvent, or emulsifier which has been approved by the UnitedStates Food and Drug Administration as being acceptable for use inhumans or domestic animals.

“Pharmaceutically acceptable salts” refers to either “pharmaceuticallyacceptable acid addition salts” or “pharmaceutically acceptable baseaddition salts” depending upon the actual structure of the compound.When a compound of Formula (I) has a basic functional group, e.g., anamine group, then a “pharmaceutically acceptable salt” may refer to anacid addition salt of the amine group. Such salts refer to any non-toxicorganic or inorganic acid addition salt of the compounds of thisdisclosure or any of its intermediates. Illustrative inorganic acidswhich form suitable salts include hydrochloric, hydrobromic, sulphuric,and phosphoric acid and acid metal salts such as sodium monohydrogenorthophosphate, and potassium hydrogen sulfate. Illustrative organicacids, which form suitable salts include the mono-, di-, andtricarboxylic acids. Illustrative of such acids are for example, acetic,glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic,tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic,hydroxy-benzoic, phenylacetic, cinnamic, salicylic, 2-phenoxybenzoic,p-toluenesulfonic acid, and sulfonic acids such as methane sulfonic acidand 2-hydroxyethane sulfonic acid. Such salts can exist in either ahydrated or substantially anhydrous form. In general, the acid additionsalts of these compounds are soluble in water and various hydrophilicorganic solvents. Basic nitrogen containing groups may be quarternizedwith agents such as lower alkyl halides (e.g., methyl, ethyl, and butylchlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl,diethyl, and dibutyl sulfates), long chain halides (e.g., decyl, lauryl,and stearyl chlorides, bromides and iodides), aralkyl halides (e.g.,benzyl and phenethyl bromides), and others. When a compound of Formula(I) has an acidic functional group, e.g., a carboxylic acid group, thena “pharmaceutically acceptable salt” may refer to a base addition saltof the acid group. Such basic salts refer to any non-toxic organic orinorganic base addition salt of the compounds of this disclosure or anyof its intermediates. Exemplary basic salts include ammonium salts,alkali metal salts such as sodium, lithium, and potassium salts,alkaline earth metal salts such as calcium and magnesium salts, saltswith organic bases (for example, organic amines) such asdicyclohexylamine, t-butyl amine, choline, and salts with amino acidssuch as arginine, lysine and the like. The counterion of the carboxylicor other acidic group may be a quarternized nitrogen-containing group.

“Prodrug” refers to a compound (e.g., a drug precursor) that istransformed in vivo to provide a compound of the present disclosure or apharmaceutically acceptable salt of the compound. The transformation mayoccur by, for example, metabolic or chemical processes, such as throughhydrolysis in blood. Prodrugs include a bio-reversible derivative of acompound of Formula I of the present disclosure. Prodrugs can alter thesolubility, lipophilicity and in-vivo distribution of drugs. Bydeliberately altering these key properties, it may be possible toimprove absorption, enhance onset time, reduce first pass metabolism,allow development of aqueous IV formulations and achieve targeteddelivery. In addition, prodrugs are useful in improving transdermaldelivery, masking taste, minimizing pain on injection, improvingstability, etc. In situations where the pharmacophore itself leads topoor delivery properties, prodrugs are one of the few strategies thatcan be used to salvage the highly active compound.

Included within the scope of the present disclosure are all prodrugs ofthe compounds of Formula (1) that can be prepared by the standardmethods known to one skilled in the art. Prodrugs of the compounds ofFormula (1) may be prepared following the methods described in, e.g.,“Prodrugs of phosphates, phosphonates, and phosphinates”, Krise J P,Stella V J, Advanced Drug Delivery Reviews, 19: (2) 287-310 May 22,1996; “Targeted Prodrug Design to Optimize Drug Delivery”. Hyo-Kyung Hanand Gordon Amidon. AAPS PharmSci 2000; 2 (1) article 6; “Prodrugs”, L.Prokai and K. Prokai-Tatrai, Chapter 12 in Injectable Drug Development:Techniques to Reduce Pain and Irritation, Interpharm Press, BuffaloGrove, Ind., 1999; “Improved oral drug delivery: Solubility limitationsovercome by the use of prodrugs”, Fleisher D, Bong R, Stewart B H,Advanced Drug Delivery Reviews, 19: (2) 115-130 May 22, 1996;“Permeable, water-soluble, non-irritating prodrugs of chemotherapeuticagents with oxaalkanoic acids”, PCT Int. Publication No. WO 00/67801; T.Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems” (1987) vol.14 of the A.C.S. Symposium Series, and “Bioreversible Carriers in DrugDesign”, (1987) Edward B. Roche, ed., American PharmaceuticalAssociation and Pergamon Press.

“Solvate” refers to a physical association of a compound of thisdisclosure with one or more solvent molecules. One or more compound ofthe disclosure may exist in solvated as well as unsolvated forms, wheresolvated forms are associated with pharmaceutically acceptable solventssuch as water, ethanol and the like. All such solvated and unsolvatedforms are within the scope of the compounds of Formula (1). The physicalassociation involves varying degrees of ionic and covalent bondingincluding hydrogen bonding. In certain instances the solvate will becapable of isolation. This may happen when the one or more solventmolecules are incorporated into the crystal lattice of a crystallinesolid comprising a compound of the present disclosure. Reference to“solvate” encompasses both solution-phase and isolatable solvates.Reference to “solvate” encompasses hemisolvates. Non-limiting examplesof solvates including methanolates, ethanolates and hydrates, wherehydrates refer to solvates wherein the associated solvent molecule iswater. A compound of the present disclosure may optionally be convertedto a corresponding solvate form by methods known in the art. Anexemplary, non-limiting process for preparing a solvate involvesdissolving the inventive compound in a selected amount of a desiredsolvent (organic or water or mixtures thereof) at temperature that ishigher than room temperature, and then cooling the solution at a ratethat is sufficiently slow that crystals are formed, where the crystalsmay be isolated. See, e.g., M. Caira et al. J. Pharmaceutical Science(2004) v.93(3) pp. 601-611; E. C. Tonder et al. AAPS Pharm. Sci. Tech.(2004, Feb. 23), v.5(1) p.E12; and A. L. Bingham et al. Chem. Commun.(2001) pp. 603-604, each of which provides a process for preparingselected solvates.

“Subject” refers to mammals, e.g., humans, as well as livestock. Thesubject may also be referred to as a patient.

“Substituents” refer to monovalent groups that may be attached to amentioned radical. For example, a “substituted phenyl” refers to aphenyl ring having 1, 2, 3 or 4 substituents attached to the phenylring. Substituents may be selected from halogen, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, —OH, —O(C₁-C₆alkyl),—O(C₁-C₆haloalkyl), —O(C₁-C₆hydroxyalkyl), —S(C₁-C₆alkyl),—S(C₁-C₆haloalkyl), —S(C₁-C₆hydroxyalkyl), cyano, amino (—NH₂), formyl(—CHO), carboxylic acid (—COOH), carboxylate ester (—COOR where R is aC₁-C₁₀ alkyl group). Likewise, a 5- or 6-membered substitutedheterocycle refers to a heterocyclic radical where at least one of thering atoms is bonded to a substituent as defined herein.

“Therapeutically effective amount” refers to the amount of a compoundthat, when administered to a mammal for a therapeutic purpose, issufficient to effect such therapy for the disease or condition. The“therapeutically effective amount” will vary depending on the compound,the condition and its severity and the age, weight, etc., of the mammalto be treated.

“Treating” or “treatment” of a condition includes: (1) preventing thecondition, i.e. causing the clinical symptoms or signs of the diseasenot to develop in a mammal that may be exposed to or predisposed to thecondition but does not yet experience or display symptoms/signs of thecondition; (2) inhibiting the condition, i.e., arresting or reducing thedevelopment of the condition or its clinical symptoms/signs, such asstopping the recurrence of the condition in a subject that has thecondition; or (3) relieving the condition, i.e., causing regression ofthe condition or its clinical symptoms/signs. Thus, “treating” or“treatment” means an alleviation of symptoms associated with a disease,disorder or condition, or halt of further progression or worsening ofthose symptoms. Depending on the disease and condition of the patient,the term “treatment” as used herein may include one or more of curative,palliative and prophylactic treatment. Treatment can also includeadministering a pharmaceutical formulation of the present disclosure incombination with other therapies. The compounds of the disclosure canalso be administered in conjunction with other drugs and/or therapies.

It is to be understood that the terminology used herein is for thepurpose of describing specific embodiments only and is not intended tobe limiting. It is further to be understood that unless specificallydefined herein, the terminology used herein is to be given itstraditional meaning as known in the relevant art.

Reference throughout this specification to “one embodiment” or “anembodiment” and variations thereof means that a particular feature,structure, or characteristic described in connection with the embodimentis included in at least one embodiment. Thus, the appearances of thephrases “in one embodiment” or “in an embodiment” in various placesthroughout this specification are not necessarily all referring to thesame embodiment. Furthermore, the particular features, structures, orcharacteristics may be combined in any suitable manner in one or moreembodiments.

As used in this specification and the appended claims, the singularforms “a,” “an,” and “the” include plural referents, i.e., one or more,unless the content and context clearly dictates otherwise. It shouldalso be noted that the conjunctive terms, “and” and “or” are generallyemployed in the broadest sense to include “and/or” unless the contentand context clearly dictates inclusivity or exclusivity as the case maybe. Thus, the use of the alternative (e.g., “or”) should be understoodto mean either one, both, or any combination thereof of thealternatives. In addition, the composition of “and” and “or” whenrecited herein as “and/or” is intended to encompass an embodiment thatincludes all of the associated items or ideas and one or more otheralternative embodiments that include fewer than all of the associateditems or ideas.

Unless the context requires otherwise, throughout the specification andclaims that follow, the word “comprise” and synonyms and variantsthereof such as “have” and “include”, as well as variations thereof suchas “comprises” and “comprising” are to be construed in an open,inclusive sense, e.g., “including, but not limited to.” The term“consisting essentially of” limits the scope of a claim to the specifiedmaterials or steps, or to those that do not materially affect the basicand novel characteristics of the claimed disclosure.

As described herein, for simplicity, a patient, clinician, or anotherhuman may in some cases be described in the context of the male gender.It is understood that a medical practitioner can be of any gender, andthe terms “he,” “his,” “himself,” and the like as used herein are to beinterpreted broadly inclusive of all known gender definitions.

Any headings used within this document are only being utilized toexpedite its review by the reader, and should not be construed aslimiting the invention or disclosure or claims in any manner. Thus, theheadings and Abstract of the Disclosure provided herein are forconvenience only and do not interpret the scope or meaning of theembodiments.

In one aspect the present disclosure provides compounds of formula (1)

or a pharmaceutically acceptable enantiomer, diastereomer, salt, orsolvate thereof, wherein:

Ar is a 9- or 10-membered bicyclic aromatic ring system, where Ar isoptionally substituted with one, two or three substituents;

L is selected from a direct bond and methylene;

R¹ is selected from hydrogen, halide, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆alkoxy, C₃-C₆cycloalkoxy and C₁-C₆alkoxy substituted withC₃-C₆cycloalkyl;

A is selected from a direct bond, —CH₂— and —CH₂CH₂—;

E is selected from —C(O)—R², C(OR³)R⁴R⁵ and CH(R⁶)NR⁷R⁸;

R² is selected from methyl, ethyl and phenyl;

R³ is selected from hydrogen, alkyl and substituted alkyl;

R⁴ is selected from hydrogen, alkyl and phenyl;

R⁵ is selected from C₁-C₇alkyl, C₁-C₇haloalky, phenyl and substitutedphenyl;

R⁶ is selected from hydrogen, methyl, halogenated methyl and ethyl;

R⁷ is hydrogen; and

R⁸ is hydrogen, methyl or ethyl;

with the proviso that together, R⁷ and R⁸ may form a 5 or 6-membered,optionally substituted, heterocycle.

For ease of discussion, formula (1) is sometimes written herein as:

wherein Ar1 and Art are used in order to refer distinctively to one ofthe two aromatic rings. Also for each of discussion, Ar1, which is 9- or10-membered bicyclic aromatic ring system, may be referred to as anaromatic ring.

Included within the scope of compounds of formula (1) arepharmaceutically acceptable enantiomers, diastereomers, salts andsolvates thereof. When a compound of formula (1) contains a chiralcenter, it may exist in either the (R) or (S) configuration and thusgive rise to two enantiomeric forms. In one embodiment, the presentdisclosure provide a compound of claim 1 as a racemic mixture of twoenantiomers of compounds of formula (1). In one embodiment, the presentdisclosure provides a compound of formula (1) as a non-racemic mixtureof enantiomers of compounds of formula (1), i.e., both the (R) and (S)enantiomers are present together in admixture, but the molar (R):(S)ratio does not equal 1. In one embodiment, the present disclosureprovides a compound of formula (1) as an isolated (S) enantiomer, i.e.,not in admixture with the corresponding (R) enantiomer or in admixturewith less than 1% of the (R) enantiomer. In one embodiment, the presentdisclosure provides a compound of formula (1) as an isolated (R)enantiomer, i.e., not in admixture with the corresponding (S) enantiomeror in admixture with less than 1% of the (S) enantiomer.

In compounds of formula (1), Ar (Ar1) represents a 9- or 10-memberedbicyclic aromatic ring system, where Ar is optionally substituted withone, two or three substituents. A bicyclic ring system refers to amoiety having two rings that are fused to one another, and a bicyclicaromatic ring refers to a moiety having two rings fused together whereat least one, and optionally two (both) of the rings is an aromaticring. In one embodiment, only one of the two rings of the bicyclicaromatic ring system is an aromatic ring. In one embodiment, both ringsof the bicyclic aromatic ring system are aromatic rings. That the ringsystem is 9- or 10-membered refers to the number of atoms that form thering system. For example, a 6-membered ring fused to a 5-membered ringprovides a 9-membered ring system, while a 6-membered ring fused to a6-membered ring provides a 10-membered ring system.

In one embodiment, Ar1 is a 9-membered bicyclic aromatic ring system,wherein a five membered ring is fused to a six membered ring. Examplesof 9-membered Ar groups according to the present disclosure includebenzofuran, 1,3-benzoxazole, furo[3,2-b]pyridine, furo[3,2-c]pyridine,furo[2,3-c]pyridine, furo[2,3-b]pyridine, indole, 1H-benzimidazole,1H-pyrrolo[3,2-b]pyridine, 1H-pyrrolo[3,2-c]pyridine,1H-pyrrolo[2,3-c]pyridine, 1H-pyrrolo[2,3-b]pyridine, benzothiophene,1,3-benzothiazole, thienol[3,2-b]pyridine, thieno[3,2-c]pyridine,thieno[2,3-c]pyridine, benzoxadiazole, benzothiadiazole, benzisoxazole,benzotriazole and thieno[2,3-b]pyridine. Each of the listed 9-memberedring systems may be an Ar group in compounds of formula (1), where eachof these ring systems is optionally substituted with one, two or threesubstituents.

In another embodiment, Ar is a 10-membered bicyclic aromatic ring systemwherein a six membered ring is fused to another six membered ring.Examples of 10-membered Ar groups according to the present disclosureinclude naphthalene, quinoline, quinazoline, quinoxaline,1,5-naphthyridine, 1,6-naphthyridine, 1,7-naphthyridine,1,8-naphthyridine, isoquinoline, phthalazine, 2,6-naphthyridine and2,7-naphthyridine. Each of the listed 10-membered ring systems may be anAr group in compounds of formula (1), where each of these ring systemsis optionally substituted with one, two or three substituents.

In one optional embodiment, compounds of formula (1) have Ar as1,3-benzothiazole. In another optional embodiment, compounds of formula(1) have Ar selected from 1,3-benzoxazole and quinoline.

A substituent on Ar refers to a monovalent group that may be attached toany of the ring atoms of the Ar group. In one embodiment, substituentsmay be selected from halide, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy,C₁-C₄haloalkoxy, C₁-C₄thioalkyl, C₁-C₄thiohaloalkyl, C₁-C₄hydroxyalkyl,—SO₂(C₁-C₄alkyl), cyano, carboxylic acid and C₁-C₄carboxyic ester. Inone embodiment, Ar does not have any substituents. In one embodiment, Aris mono-substituted, where optionally the one substituent may beselected from those listed above. For example, in one embodiment, Arcontains a single substituent which is C₁-C₄thioalkyl, e.g., —S-methyl.In another embodiment, Ar is di-substituted, where optionally the twosubstituents may be independently selected from those listed above. In afurther embodiment, Ar is tri-substituted, where optionally the threesubstituents may be independently selected from those listed above. Inone optional embodiment, the compounds of formula (1) have a singlesubstituent on Ar, where that single substituent is —S—CH₃.

The Ar group (sometimes referred to herein as Ar1) is joined to acentral benzene ring (sometimes referred to herein as Ar2) in compoundsof formula (1) via an —L—O— group. In one embodiment, L is a directedbond, so that the Ar group is joined to a central benzene ring incompounds of formula (1) via an ether (—O—) linkage. In anotherembodiment, L is methylene, so that the Ar group is joined to a centralbenzene ring in compounds of formula (1) via a —CH₂—O— linkage.

The central benzene ring in formula (1) is bonded to R¹, where R¹ isselected from hydrogen, halide, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy,and C₁-C₆alkoxy substituted with C₃-C₆cycloalkyl. In one embodiment, R¹is hydrogen, so that the central benzene ring (Ar2) may be said to beunsubstituted. In another embodiment, R¹ is not hydrogen, so that thecentral benzene ring is substituted. In one embodiment R¹ is halide,e.g., fluoride. In another embodiment, R¹ is C₁-C₆alkyl, e.g., methyl orethyl. In one embodiment, R¹ is C₁-C₆haloalkyl, e.g., trifluoromethyl.In one embodiment, R¹ is C₁-C₆alkoxy, e.g., methoxy or ethoxy. In oneembodiment, R¹ is C₃-C₆cycloalkoxy, e.g., cyclopropyloxy, cyclobutyloxyor cyclopentyloxy. In one embodiment, R¹ is C₁-C₆alkoxy substituted withC₃-C₆cycloalkyl, such as —O—CH₂-cyclopropyl where —O—CH₂ is a C₁ alkoxythat is substituted with a C₃ cycloalkyl (cyclopropyl).

In compounds of formula (1), a central aromatic ring (benzene) issubstituted with R¹ as descried above, as well as the group denoted as—A—E. In effect, A links together the E group and the central aromaticring. The A group is selected from a direct bond, methylene andethylene. Independent of the selection of the A group, the E group isselected from —C(O)—R², i.e., a carbonyl group bonded to R², C(OR³)R⁴R⁵,i.e., a carbon to which each of OR³, R⁴ and R⁵ is bonded, andCH(R⁶)NR⁷R⁸, i.e., a carbon to which each of hydrogen, R⁶ and NR⁷R⁸ isbonded. For example, A may be a direct bond while E is selected from—C(O)—R², C(OR³)R⁴R⁵ and CH(R⁶)NR⁷R⁸, i.e., in one embodiment A—E is—C(O)—R², while in another embodiment A—E is C(OR³)R⁴R⁵, and in afurther embodiment A—E is CH(R⁶)NR⁷R⁸. Alternatively, A may be methylenewhile E is selected from —C(O)—R², C(OR³)R⁴R⁵ and CH(R⁶)NR⁷R⁸, i.e., inone embodiment A—E is CH₂—C(O)—R², while in another embodiment A—E isCH₂—C(OR³)R⁴R⁵, and in a further embodiment A—E is CH₂—CH(R⁶)NR⁷R³. As afurther embodiment, A may be ethylene while E is selected from —C(O)—R²,C(OR³)R⁴R⁵ and CH(R⁶)NR⁷R⁸, i.e., in one embodiment A—E isCH₂CH₂—C(O)—R², while in another embodiment A—E is CH₂CH₂—C(OR³)R⁴R⁵,and in a further embodiment A—E is CH₂CH₂—CH(R⁶)NR⁷R⁸. In oneembodiment, A is a direct bond. In another embodiment, A is —CH₂—. Inone embodiment, A is —CH₂CH₂—. In another embodiment, R⁵ istrifluoromethyl.

In one embodiment, E is —C(O)—R², where R² is methyl, ethyl or phenyl,e.g., E may be any of C(O)CH₃, i.e., acetyl, C(O)CH₂CH₃, or C(O)phenyl,i.e., benzoyl. Thus, in one embodiment, —A—E is —C(O)—R² when A is adirect bond. In another embodiment, —A—E is CH₂—C(O)—R² when A ismethylene, e.g., —CH₂—C(O)CH₃, or —CH₂C(O)CH₂CH₃, or —CH₂(C(O)phenyl. Ina further embodiment, A—E is CH₂CH₂C(O)—R² when A is ethylene, e.g.,—CH₂CH₂C(O)CH₃ or —CH₂CH₂C(O)CH₂CH₃ or CH₂CH₂C(O)phenyl.

In one embodiment, E is C(OR³)R⁴R⁵, where R³ is selected from hydrogen,alkyl and substituted alkyl; R⁴ is selected from hydrogen, alkyl andphenyl; and R⁵ is selected from C₁-C₇alkyl, C₁-C₇haloalky, phenyl andsubstituted phenyl. In one embodiment, R⁵ is trifluoromethyl and R³ ishydrogen.

In one embodiment, E is CH(R⁶)NR⁷R⁸, where R⁶ is selected from hydrogen,methyl, halogenated methyl and ethyl; R⁷ is hydrogen; and R⁸ ishydrogen, methyl or ethyl. For example, in one embodiment, E is selectedfrom CH(R⁶)NH₂, CH(R⁶)NH(CH₃) and CH(R⁶)NH(CH₂CH₃). In one embodiment,R⁷ and R⁸ together, along with the nitrogen atom to which they are bothattached, may form a 5 or 6-membered, optionally substituted,heterocycle, where the heterocycle will include the nitrogen to whichboth R⁷ and R⁸ are attached, as well as one or more, e.g., two,non-carbon atoms, e.g., oxygen or nitrogen. Thus, optionally, R⁷ and R⁸together form a 5 or 6-membered, optionally substituted, heterocyclicring, which includes the nitrogen of the NR⁷R⁸ group. Exemplary5-membered rings are pyrrolidine and unsaturated analogs thereof, e.g.,2,5-dihydro-1H-pyrrole. Thus, —NR⁷R⁸ may represent2,5-dihydro-1H-pyrrole. Exemplary 6-membered heterocyclic rings arepiperidine and unsaturated analogs thereof, e.g.,1,2,3,4-tetrahydropyridine, and piperazine. The 5-membered heterocyclicring and 6-membered heterocyclic ring will each have at least onenitrogen atom, and optionally may have a second heteroatom ring atom,e.g., a heteroatom selected from oxygen, nitrogen and sulfur. The5-membered heterocyclic ring and 6-membered heterocyclic ring may besubstituted as described herein. In one embodiment, substituents may beselected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl,hydroxyl (—OH), oxo (═O), —O(C₁-C₆alkyl), —O(C₁-C₆haloalkyl),—O(C₁-C₆hydroxyalkyl), —S(C₁-C₆alkyl), —S(C₁-C₆haloalkyl),—S(C₁-C₆hydroxyalkyl), cyano, amino (—NH₂), formyl (—CHO), carboxylicacid (—COOH), carboxylate ester (—COOR where R is a C₁-C₁₀ alkyl group).Thus, in one embodiment, E is CH(R⁶)NR⁷R⁸, where (i) R⁶ is selected fromhydrogen, methyl, halogenated methyl and ethyl; and R⁷ is hydrogen; andR⁸ is selected from hydrogen, methyl and ethyl, or (ii) R⁷ and R⁸together, along with the nitrogen atom to which they are both attached,form a 5 or 6-membered heterocycle, which is optionally substituted,where the heterocycle will include the nitrogen to which both R⁷ and R⁸are attached, as well as one or more, e.g., two, non-carbon atoms, e.g.,oxygen or nitrogen.

In compounds of formula (1), Ar may be unsubstituted aryl, or it mayhave one, two or three substituents. In one embodiment, Ar has nosubstituents. In another embodiment, Ar has one substituent. In yetanother embodiment, Ar has two substituents. In a further embodiment, Arhas three substituents. When Ar has no substituents, the presentdisclosure provides compounds of formula (1)

and pharmaceutically acceptable salts thereof, wherein: Ar is a 9- or10-membered unsubstituted bicyclic aromatic ring system; L is selectedfrom a direct bond and methylene; R¹ is selected from hydrogen, halide,C₁-C₆alkyl, C₁-C₆haloalkyl and C₁-C₆alkoxy; A is selected from a directbond, —CH₂— and —CH₂CH₂—; E is selected from —C(O)—R², C(OR³)R⁴R⁵ andCH(R⁶)NR⁷R³; R² is selected from methyl, ethyl and phenyl; R³ isselected from hydrogen, alkyl and substituted alkyl; R⁴ is selected fromhydrogen, alkyl and phenyl; R⁵ is selected from C₁-C₇alkyl,C₁-C₇haloalkyl (e.g., trifluoromethyl), phenyl and substituted phenyl;R⁶ is selected from hydrogen, methyl, halogenated methyl and ethyl; R⁷is hydrogen; and R⁸ is hydrogen, methyl or ethyl; with the proviso thattogether, R⁷ and R⁸ may form a 5 or 6-membered, optionally substituted,heterocycle. In one such embodiment, A is ethylene and E is —C(O)—R²,while R¹ is selected from halide and alkoxy so as to provide compound,when Ar—L—O is benzoxazol-2-yloxy so as to provide compounds of theformula

for example, a compound of the formula

In another such embodiment, A is ethylene and E is C(OR³)R⁴R⁵ where R³is hydrogen, R⁴ is alkyl, e.g., ethyl, and R⁵ is C₁-C₇haloalky, e.g.,trifluoromethyl, while R¹ is C₁-C₄alkoxy, so as to provide compounds,when Ar—L—O is 1,3-benzothiazol-2-yloxy, of the formula

for example, the compounds

In another such embodiment, A is ethylene and E is C(OR³)R⁴R⁵ where R³is hydrogen, R⁴ is alkyl, e.g., methyl, and R⁵ is C₁-C₇haloalky, e.g.,trifluoromethyl, while R¹ is C₁-C₄alkoxy, so as to provide compounds,when Ar—L—O is 1,3-benzothiazol-2-yloxy, of the formula

for example, a compound of the formula

In another embodiment, A is ethylene and E is C(OR³)R⁴R⁵ where R³ isselected from hydrogen, alkyl and substituted alkyl; R⁴ is hydrogen, andR⁵ is selected from C₁-C₇alkyl, C₁-C₇haloalky, phenyl and substitutedphenyl; while R¹ is selected from hydrogen, halide, C₁-C₆alkyl,C₁-C₆haloalkyl and C₁-C₆alkoxy, so as to provide compounds, e.g., whenAr—L—O is 1,3-benzothiazol-2-yloxy, of the formula

for instance compounds of the formula

In another embodiment, R¹ may be hydrogen so as to provide compounds ofthe formula

In another embodiment wherein Ar is unsubstituted, the presentdisclosure provides compounds having the formula

including those having the formula

e.g., when R¹ is alkoxy, the compounds

In another embodiment, Ar is unsubstituted, R1 is hydrogen, A isethylene, E is C(OR³)R⁴R⁵; R³ is selected from hydrogen, alkyl andsubstituted alkyl; R⁴ is selected from hydrogen, alkyl and phenyl; andR⁵ is selected from C₁-C₇alkyl, C₁-C₇haloalkyl, phenyl and substitutedphenyl; so as to provide compounds, e.g., of the formula

e.g., the compounds

In another embodiment, Ar is unsubstituted and R¹ is C₂-C₄alkoxy, so asto provide compounds, e.g., of the formula.

e.g., the compound

Other compounds of the present disclosure having an unsubstituted Argroup include:

In another embodiment, Ar is unsubstituted and E is —C(OH)(CF₃)(CH₂CH₃),so as to provide compounds of the formula

e.g., the compound

Other compound of the present disclosure having an unsubstituted Argroup have A equal to ethylene and E is C(O)-phenyl, for example,compounds of the formula

e.g., the compound

In another embodiment, Ar is unsubstituted and A is a direct bond, toprovide compounds, e.g., having the formula

e.g., the compound

Other compounds wherein A is a direct bond have R1 as hydrogen, so as toprovide compounds having the formula

such as compounds having the formula

which includes compounds, using benzothiazole as an exemplary Ar group,having the formula

e.g., the compounds

As mentioned above, in compounds of formula (1), Ar may be unsubstitutedaryl, or it may have one, two or three substituents. When Ar hassubstituents, the present disclosure provides compounds of formula (1)

and pharmaceutically acceptable salts thereof, wherein: Ar is a 9- or10-membered substituted bicyclic aromatic ring system, having one, twoor three substituents; L is selected from a direct bond and methylene;R¹ is selected from hydrogen, halide, C₁-C₆alkyl, C₁-C₆haloalkyl andC₁-C₆alkoxy; A is selected from a direct bond, —CH₂— and —CH₂CH₂—; E isselected from —C(O)—R², C(OR³)R⁴R⁵ and CH(R⁶)NR⁷R⁸; R² is selected frommethyl, ethyl and phenyl; R³ is selected from hydrogen, alkyl andsubstituted alkyl; R⁴ is selected from hydrogen, alkyl and phenyl; R⁵ isselected from C₁-C₇alkyl, C₁-C₇haloalkyl (e.g., trifluoromethyl), phenyland substituted phenyl; R⁶ is selected from hydrogen, methyl,halogenated methyl and ethyl; R⁷ is hydrogen; and R⁸ is hydrogen, methylor ethyl; with the proviso that together, R⁷ and R⁸ may form a 5 or6-membered, optionally substituted, heterocycle. In one such embodiment,Ar has one or two substituents. Optionally, A is selected from CH₂ andCH₂CH₂ so as to provide, for example, compounds of the formula

including compounds wherein L is a direct bond to provide compoundshaving the formula

which includes compounds of the formula

wherein R⁹ represents one or two substituents on Ar, independentlyselected at each occurrence, where R³ may be, for example, hydrogen, soas to provide compounds of the formula.

wherein R⁴ is methyl or ethyl, and compounds of the formula

including compounds having the formula

e.g., the compound

In one embodiment wherein Ar is substituted with one or two R⁹ groups,the present disclosure provides compounds having the formula

including compounds wherein R⁹ is thiomethyl, to provide compoundshaving the formula

the compound

Other compounds of the present disclosure having methoxy as R¹ andsubstitution on Ar include those of the formula

including the compounds

Further compounds of the present disclosure having substitution on Arinclude compounds having the formula

e.g., the compound

In other embodiments, Ar is substituted and R¹ is selected from halideand alkoxy to provide, e.g., a compounds of the formulae

In one embodiment, the compounds of the disclosure include both ofhydroxyl and trifluoromethyl as components of the “E” group. Forexample, the present disclosure provides compounds of the formula

and pharmaceutically acceptable salts thereof, wherein: Ar is a 9- or10-membered bicyclic aromatic ring system, where Ar is optionallysubstituted with one, two or three substituents; L is selected from adirect bond and methylene; R¹ is selected from hydrogen, halide,C₁-C₄alkyl, C₁-C₄haloalkyl and C₁-C₄alkoxy; A is selected from a directbond, —CH₂— and —CH₂CH₂—; E is C(OR³)R⁴R⁵ where R³ is hydrogen while R⁵is trifluoromethyl, so that E is C(OH)(CF₃)R⁴; and R⁴ is selected fromhydrogen, methyl and ethyl. Optionally, a compound of formula (1) mayadditionally be characterized by one or more of the following: R⁵ isC₁-C₇alkyl; R⁵ is methyl; R⁵ is ethyl; R⁵ is C₁-C₇haloalkyl; R⁵ isphenyl; A is —CH₂CH₂— and R⁵ is C₁-C₇alkyl; A is —CH₂CH₂— and R⁵ ismethyl; A is —CH₂CH₂— and R⁵ is ethyl; A is —CH₂CH₂— and R⁵ isC₁-C₇haloalkyl; A is —CH₂CH₂— and R⁵ is phenyl; L is a direct bond, A is—CH₂CH₂— and R⁵ is C₁-C₇alkyl; L is a direct bond, A is —CH₂CH₂— and R⁵is methyl; L is a direct bond, A is —CH₂CH₂— and R⁵ is ethyl; L is adirect bond, A is —CH₂CH₂— and R⁵ is C₁-C₇haloalkyl (e.g.,trifluoromethyl); L is a direct bond, A is —CH₂CH₂— and R⁵ is phenyl; Aris unsubstituted benzothiazol-2-yl; Ar is benzothiazol-2-yl having onesubstituent; Ar is benzothiazol-2-yl having two substituents; and Ar isbenzothiazol-2-yl having three substituents. In addition, the presentdisclosure provides the following exemplary compounds that includehydroxyl and trifluoromethyl as components of the “E” group:

In another embodiment, the present disclosure provides compounds offormula (1)

including pharmaceutically acceptable salts thereof, wherein Ar1 is a6-benzothiazole, where Ar1 is optionally substituted with one or twosubstituents, and L is a direct bond, so that formula (1) has thestructure;

where R¹ is selected from hydrogen, halide and alkoxy; A is selectedfrom a direct bond, —CH₂— and —CH₂CH₂—; E is selected from —C(O)—R²,C(OR³)R⁴R⁵ and CH(R⁶)NR⁷R⁸; R² is selected from methyl, ethyl andphenyl; R³ is selected from H and a hydroxyl protecting group; R⁴ isselected from hydrogen, methyl and ethyl; R⁵ is selected from methyl,halogenated methyl (e.g., trifluoromethyl) ethyl and phenyl; R⁶ isselected from hydrogen, methyl, halogenated methyl and ethyl; R⁷ ishydrogen; and R⁸ is methyl or ethyl; with the proviso that together, R⁷and R⁸ may form a 5 or 6-membered optionally substituted heterocycle. Inaddition, the present disclosure provides the following exemplarycompounds that include 6-benzothiazole as the Ar group:

In another embodiment, the present disclosure provides compounds offormula (1)

and pharmaceutically acceptable salts thereof, wherein Ar1 is anaphthalene radical, or a heterocyclic analog thereof, where Ar1 isoptionally substituted with one or two substituents, and L is optionallya methylene group (—CH₂—), where R¹ is selected from hydrogen, halideand alkoxy; A is selected from a direct bond, —CH₂— and —CH₂CH₂—; E isselected from —C(O)—R², C(OR³)R⁴R⁵ and CH(R⁶)NR⁷R³; R² is selected frommethyl, ethyl and phenyl; R³ is selected from H and a hydroxylprotecting group; R⁴ is selected from hydrogen, methyl and ethyl; R⁵ isselected from methyl, halogenated methyl (e.g., trifluoromethyl), ethyland phenyl; R⁶ is selected from hydrogen, methyl, halogenated methyl andethyl; R⁷ is hydrogen; and R⁸ is methyl or ethyl; with the proviso thattogether, R⁷ and R⁸ may form a 5 or 6-membered optionally substitutedheterocycle. In addition, the present disclosure provides the followingexemplary compounds that include naphthyl or heterocyclic analogs ofnaphthyl as the Ar group:

wherein R¹ is selected from hydrogen, halide and alkoxy; A is selectedfrom a direct bond, —CH₂— and —CH₂CH₂—; E is selected from —C(O)—R²,C(OR³)R⁴R⁵ and CH(R⁶)NR⁷R⁸; R² is selected from methyl, ethyl andphenyl; R³ is selected from H and a hydroxyl protecting group; R⁴ isselected from hydrogen, methyl and ethyl; R⁵ is selected from methyl,halogenated methyl (e.g., trifluoromethyl), ethyl and phenyl; R⁶ isselected from hydrogen, methyl, halogenated methyl and ethyl; R⁷ ishydrogen; and R⁸ is methyl or ethyl; with the proviso that together, R⁷and R⁸ may form a 5 or 6-membered optionally substituted heterocycle,such as compounds of the formula

wherein R¹ is selected from hydrogen, halide and alkoxy; R³ is selectedfrom H and a hydroxyl protecting group; R⁴ is selected from hydrogen,methyl and ethyl; R⁵ is selected from methyl, halogenated methyl (e.g.,trifluoromethyl), ethyl and phenyl, e.g.,

And in addition, the present disclosure provides the following exemplarycompounds that include naphthyl or heterocyclic analogs of naphthyl asthe Ar group, such as compounds of the formula:

wherein R¹ is selected from hydrogen, halide and alkoxy; A is selectedfrom a direct bond, —CH₂— and —CH₂CH₂—; E is selected from —C(O)—R²,C(OR³)R⁴R⁵ and CH(R⁶)NR⁷R⁸; R² is selected from methyl, ethyl andphenyl; R³ is selected from H and a hydroxyl protecting group; R⁴ isselected from hydrogen, methyl and ethyl; R⁵ is selected from methyl,halogenated methyl (e.g., trifluoromethyl), ethyl and phenyl; R⁶ isselected from hydrogen, methyl, halogenated methyl and ethyl; R⁷ ishydrogen; and R⁸ is methyl or ethyl; with the proviso that together, R⁷and R⁸ may form a 5 or 6-membered optionally substituted heterocycle,including compounds of the formula

wherein R¹ is selected from hydrogen, halide and alkoxy and R² isselected from methyl, ethyl and phenyl, such as the compound of theformula

In one embodiment, the compounds of the disclosure have a nitrogen atomas part of the E group, and more specifically have E is —CH(R⁶)NR⁷R⁸.For example, the present disclosure provides compounds of the formula(1)

and pharmaceutically acceptable salts thereof, wherein: Ar is a 9- or10-membered bicyclic aromatic ring system, where Ar is optionallysubstituted with one or two substituents; L is selected from a directbond and methylene; R¹ is selected from hydrogen, halide and alkoxy; Ais selected from a direct bond, —CH₂— and —CH₂CH₂—; E is CH(R⁶)NR⁷R⁸; R⁶is selected from hydrogen, methyl, halogenated methyl and ethyl; R⁷ ishydrogen; and R⁸ is methyl or ethyl; with the proviso that together, R⁷and R⁸ may form a 5 or 6-membered optionally substituted heterocycle.Optionally, a compound of formula (1) may additionally be characterizedby one or more of the following: R⁷ and R⁸ form a 5 or 6-memberedoptionally substituted heterocycle, and R¹ is hydrogen; A is CH₂CH₂; R⁷and R⁸ form a 5 or 6-membered optionally substituted heterocycle, R¹ ishydrogen and A is CH₂CH₂, to provide, for example, the followingcompounds:

Optionally, such a compound of formula (1) may additionally becharacterized by specifying that A is a direct bond, so as to provide,for example, compounds of the formula:

Optionally, such a compound of formula (1) may additionally becharacterized by specifying that R¹ is not hydrogen, R⁷ is hydrogen, andR⁸ is methyl or ethyl, so as to provide, for example, a compound of theformula.

In one embodiment, the compounds of the disclosure have a carbonyl group(C(O)) as part of the E group, and more specifically have E is—CH(R⁶)NR⁷R⁸. For example, the present disclosure provides compounds ofthe formula (1)

and pharmaceutically acceptable salts thereof, wherein: Ar is a 9- or10-membered bicyclic aromatic ring system, where Ar is optionallysubstituted with one, two or three substituents; L is selected from adirect bond and methylene; R¹ is selected from hydrogen, halide,C₁-C₆alkyl, C₁-C₆haloalkyl and C₁-C₆alkoxy; A is selected from a directbond, —CH₂— and —CH₂CH₂—; E is —C(O)—R²; and R² is selected from methyl,ethyl and phenyl. For example, the present disclosure provides compoundsof the formula

wherein Ar is a 9- or 10-membered bicyclic aromatic ring system, whereAr is optionally substituted with one, two or three substituents; L isselected from a direct bond and methylene; R¹ is selected from hydrogen,halide, C₁-C₆alkyl, C₁-C₆haloalkyl and C₁-C₆alkoxy; A is —CH₂CH₂—; E is—C(O)—R²; and R² is phenyl, including compounds of the formula

wherein Ar is a 9- or 10-membered bicyclic aromatic ring system, whereAr is optionally substituted with one, two or three substituents; L isselected from a direct bond and methylene; R¹ is C₁-C₆alkoxy andspecifically methoxy; A is —CH₂CH₂—; E is —C(O)—R²; and R² is phenyl,and including compounds of the formula

wherein R¹ is selected from hydrogen, halide, C₁-C₆alkyl, C₁-C₆haloalkyland C₁-C₆alkoxy, such as the compound of the formula

In one embodiment, the compounds of the disclosure have halidesubstitution on the central aromatic ring, i.e., compounds of formula(1) wherein R¹ is halide. For example, the present disclosure providescompounds of the formula (1) In one aspect the present disclosureprovides compounds of the formula (1)

and pharmaceutically acceptable salts thereof, wherein: Ar is a 9- or10-membered bicyclic aromatic ring system, where Ar is optionallysubstituted with one, two or three substituents; L is selected from adirect bond and methylene; R¹ is halide; A is selected from a directbond, —CH₂— and —CH₂CH₂—; E is selected from —C(O)—R², C(OR³)R⁴R⁵ andCH(R⁶)NR⁷R⁸; R² is selected from methyl, ethyl and phenyl; R³ isselected from hydrogen, alkyl and substituted alkyl; R⁴ is selected fromhydrogen, alkyl and phenyl; R⁵ is selected from C₁-C₇alkyl,C₁-C₇haloalkyl (e.g., trifluoromethyl), phenyl and substituted phenyl;R⁶ is selected from hydrogen, methyl, halogenated methyl and ethyl; R⁷is hydrogen; and R⁸ is hydrogen, methyl or ethyl; with the proviso thattogether, R⁷ and R⁸ may form a 5 or 6-membered, optionally substituted,heterocycle. For example, the present disclosure provides compounds ofthe formula

wherein R¹ is halide and R² is selected from methyl, ethyl and phenyl;such as

wherein R¹ is halide, R³ is selected from hydrogen, alkyl andsubstituted alkyl; R⁴ is selected from hydrogen, alkyl and phenyl; R⁵ isselected from C₁-C₇alkyl, C₁-C₇haloalkyl (e.g., trifluoromethyl), phenyland substituted phenyl; such as

The compounds of the present disclosure are also meant to encompass allpharmaceutically acceptable compounds of formula (1) and subsetsthereof, being isotopically-labelled by having one or more atomsreplaced by an atom having a different atomic mass or mass number.Examples of isotopes that can be incorporated into the disclosedcompounds include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine, chlorine, and iodine, such as ²H, ³H, ¹¹C, ¹³C,¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I,respectively. These radiolabeled compounds could be useful to helpdetermine or measure the effectiveness of the compounds, bycharacterizing, for example, the site or mode of action, or bindingaffinity to a pharmacologically important site of action. Certainisotopically-labelled compounds of the disclosure, for example, thoseincorporating a radioactive isotope, are useful in drug and/or substratetissue distribution studies. The radioactive isotopes tritium, i.e. ³H,and carbon-14, i.e. ¹⁴C, are particularly useful for this purpose inview of their ease of incorporation and ready means of detection.Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances.Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy. Isotopically-labelled compoundsof the disclosure can generally be prepared by conventional techniquesknown to those skilled in the art or by processes analogous to thosedescribed in the Preparations and Examples as set out below using anappropriate isotopically-labelled reagent in place of the non-labeledreagent previously employed.

Often crystallizations produce a solvate of the compound of thedisclosure. As used herein, the term “solvate” refers to an aggregatethat comprises one or more molecules of a compound of the disclosurewith one or more molecules of solvent. The solvent may be water, inwhich case the solvate may be a hydrate. Alternatively, the solvent maybe an organic solvent. Thus, the compounds of the present disclosure mayexist as a hydrate, including a monohydrate, dihydrate, hemihydrate,sesquihydrate, trihydrate, tetrahydrate and the like, as well as thecorresponding solvated forms. The compound of the disclosure may be truesolvates, while in other cases, the compound of the disclosure maymerely retain adventitious water or be a mixture of water plus someadventitious solvent.

Some specific compounds of the present disclosure are provided in Table1, which identifies specific compounds by each of compound number (No.),compound structure and compound name:

TABLE 1 No. Compound Structure Compound Name 101

1-[4-(1,3-benzothiazol-2-yloxy)- 3-methoxyphenyl]pentan-3-one 102

1-[4-(1,3-benzoxazol-2-yloxy)-3- methoxyphenyl]pentan-3-one 103

1-[4-(1,3-benzothiazol-2-yloxy)- 3-methoxyphenyl]-3-(trifluoromethyl)pentan-3-ol 104

1-{3-methoxy-4-[(4- methylsulfanyl-1,3- benzothiazol-2-yl)oxy]phenyl}-3-(trifluoromethyl)pentan-3-ol 105

1-[4-(1-methyl-1H- benzimidazol-2-yloxy)-3- methoxyphenyl]-3-(trifluoromethyl)pentan-3-ol 106

1-{3-methoxy-4-[(6- methylsulfonyl-1,3- benzothiazol-2-yl)oxy]phenyl}-3-(trifluoromethyl)pentan-3-ol 107

1-{4-[(4,6-difluoro-1,3- benzothiazol-2-yl)oxy]-3- methoxyphenyl}-3-(trifluoromethyl)pentan-3-ol 108

1-{4-[(6-fluoro-1,3- benzothiazol-2-yl)oxy]-3- methoxyphenyl}-3-(trifluoromethyl)pentan-3-ol 109

1-{4-[(6-methoxy-1,3- benzothiazol-2-yl)oxy]-3- methoxyphenyl}-3-(trifluoromethyl)pentan-3-ol 110

4-[4-(1,3-benzothiazol-2-yloxy)- 3-methoxyphenyl]butan-2-one 111

4-[4-(1,3-benzothiazol-2-yloxy)- 3-methoxyphenyl]-1,1,1-trifluoro-2-methylbutan-2-ol 112

1-[4-(1,3-benzothiazol-2-yloxy)- 3-(iso-propyloxy)- phenyl]pentan-3-one113

1-[4-(1,3-benzothiazol-2-yloxy)- 3-(cyclopentyloxy)- phenyl]pentan-3-one114

1-[4-(1,3-benzothiazol-2-yloxy)- 3-(cyclopropyl-methoxy)-phenyl]pentan-3-one 115

1-[4-(1,3-benzothiazol-2-yloxy)- 3-(iso-propyloxy)phenyl]-3-(trifluoromethyl)pentan-3-ol 116

1-[4-(1,3-benzothiazol-2-yloxy)- 3-(cyclopentyloxy)-phenyl]-3-(trifluoromethyl)-pentan-3-ol 117

1-[4-(1,3-benzothiazol-2-yloxy)- 3-(cyclopropyl-methoxy)-phenyl]-3-(trifluoromethyl)- pentan-3-ol 118

4-(3-methoxy-4-{[4- (methylsulfanyl)-1,3- benzothiazol-2-yl]oxy}phenyl)butan-2-one 119

1,1,1-trifluoro-4-(3-methoxy-4- {[4-(methylsulfanyl)-1,3-benzothiazol-2-yl]oxy}phenyl)- 2-methylbutan-2-ol 120

1-[4-(1,3-benzothiazol-2-yloxy)- 3-ethoxyphenyl]-pentan-3-one 121

1-[4-(1,3-benzothiazol-2-yloxy)- 3-ethoxyphenyl]-3-(trifluoromethyl)pentan-3-ol 122

4-[4-(1,3-benzothiazol-2-yloxy)- 3-methoxyphenyl]-butan-2-ol 123

4-[4-(1,3-benzothiazol-2-yloxy)- 3-methoxyphenyl]-2- (phenyl)butan-2-ol124

4-[4-(1,3-benzothiazol-2-yloxy)- 3-methoxyphenyl]-2- methylbutan-2-ol125

4-[4-(1,3-benzoxazol-2-yloxy)-3- methoxyphenyl]butan-2-one 126

4-[4-(1,3-benzoxazol-2-yloxy)-3- methoxyphenyl]-2- methylbutan-2-ol 127

1-[4-(1,3-benzoxazol-2-yloxy)-3- methoxyphenyl]-3- methylpentan-3-ol 128

4-[4-(1,3-benzoxazol-2-yloxy)-3- methoxyphenyl]-2- phenylbutan-2-ol 129

3-[4-(1,3-benzothiazol-2-yloxy)- 3-ethoxyphenyl]-1- phenylpropan-1-one130

4-[3-ethoxy-4-(1,3- benzothiazol-2-yloxy)phenyl]-1,1,1-trifluoro-2-phenylbutan- 2-ol 131

3-[4-(1,3-benzothiazol-2-yloxy)- 3-methoxyphenyl]-1- phenylpropan-1-one132

3-[4-(1,3-benzothiazol-2-yloxy)- 3-methoxyphenyl]-1- phenylpropan-1-ol133

3-[4-(1,3-benzothiazol-2-yloxy)- 3-methoxyphenyl]-1-(trifluoromethyl)-1- phenylpropan-1-ol 134

2-{2-methoxyl-4-[3-phenyl-3- (pyrrolidin-1- yl)propyl]phenoxy}-1,3-benzothiazole 135

1-[4-(1,3-benzothiazol-2-yloxy)- 3-methoxyphenyl]pentan-3- amine 136

4-{1-[3-methoxy-4-(1,3- benzothiazol-2- yloxy)phenyl]pentan-3-yl}morpholine 137

1-[4-(1,3-benzothiazol-2-yloxy)- 3-methoxyphenyl]-2,2,2-trifluoroethanol 138

1-[4-(1,3-benzothiazol-2-yloxy)- 3-methoxyphenyl]-N-ethyl-2,2,2-trifluoroethanamine 139

2,2,2-trifluoro-1-(3-methoxy-4- {[4-(methylsulfanyl)-1,3-benzothiazol-2- yl]oxy}phenyl)ethanol 140

4-[4-(1,3-benzothiazol-2- yloxy)phenyl]-1,1,1-trifluoro-2-methylbutan-2-ol 141

4-[4-(1,3-benzothiazol-2- yloxy)phenyl]butan-2-ol 142

1-[4-(1,3-benzothiazol-2- yloxy)phenyl]-3,4- dimethylpentan-3-ol 143

1-[4-(1,3-benzothiazol-2- yloxy)phenyl]-3-methylpentan- 3-ol 144

4-[4-(1,3-benzothiazol-2- yloxy)phenyl]-2- phenylbutan-2-ol 145

4-[4-(1,3-benzothiazol-2- yloxy)phenyl]-2-(4- fluorophenyl)butan-2-ol146

1-[4-(1,3-benzoxazol-2- yloxy)phenyl]-3-methylpentan- 3-ol 147

4-[4-(1,3-benzoxazol-2- yloxy)phenyl]-2-phenylbutan-2- ol 148

1-[4-(1,3-benzothiazol-2- yloxy)phenyl]pentan-3-one 149

1-[4-(1,3-benzothiazol-2-yloxy)- 3-chlorophenyl]pentan-3-one 150

1-[4-(1,3-benzothiazol-2- yloxy)phenyl]-3- (trifluoromethyl)pentan-3-ol151

1-[4-(1,3-benzothiazol-2-yloxy)- 3-chlorophenyl]-3-(trifluoromethyl)pentan-3-ol 152

1-[4-(1,3-benzothiazol-2-yloxy)- 3-fluorophenyl]-pentan-3-one 153

1-[4-(1,3-benzothiazol-2-yloxy)- 3-(trifluoromethyl)-phenyl]pentan-3-one 154

1-[4-(1,3-benzothiazol-2-yloxy)- 3-fluorophenyl]-3-(trifluoromethyl)pentan-3-ol 155

1-[4-(1,3-benzothiazol-2-yloxy)- 3-(trifluoromethyl)-phenyl]-3-(trifluoromethyl)-pentan-3-ol 156

2-{4-[3-(pyrrolidin-1- yl)butyl]phenoxy}-1,3- benzothiazole 157

1-{4-[4-(1,3-benzothiazol-2- yloxy)phenyl]butan-2- yl}pyrrolidine-2-carboxylic acid 158

2-{4-[3-(pyrrolidin-1- yl)pentyl]phenoxy}-1,3- benzothiazole 159

1-[4-(1,3-benzothiazol-2- yloxy)phenyl]ethanone 160

1-[4-(1,3-benzothiazol-2- yloxy)phenyl]ethanol 161

2-[4-(1,3-benzothiazol-2- yloxy)phenyl]butan-2-ol 162

2-{4-[1-(pyrrolidin-1- yl)ethyl]phenoxy}-1,3- benzothiazole 163

2-[4-(1,3-benzothiazol-2- yloxy)phenyl]-1,1,1- trifluoropropan-2-ol 164

2-[4-(pyrrolidin-1- ylmethyl)phenoxy]-1,3- benzothiazole 165

1-[4-(1,3-benzothiazol-2- yloxy)benzyl]pyrrolidine-2- carboxylic acid166

1-[4-(1,3-benzothiazol-2- yloxy)phenyl]-2,2,2- trifluoroethanol 167

1-[4-(1,3-benzothiazol-2-yloxy)- 3-chlorophenyl]-2,2,2- trifluoroethanol168

1-[4-(1,3-benzothiazol-2- yloxy)phenyl]-N-ethyl-2,2,2-trifluoroethanamine 169

1-{4-[(2-methyl-1,3- benzothiazol-6- yl)oxy]phenyl}ethanone 170

1,1,1-trifluoro-2-{4-[(2-methyl- 1,3-benzothiazol-6-yl)oxy]phenyl}propan-2-ol 171

1-{4-[(2-methyl-1,3- benzothiazol-6- yl)oxy]phenyl}ethanol 172

1-[4-(1,3-benzothiazol-2-yloxy)- 3-methoxyphenyl]-ethanone 173

2-[4-(1,3-benzothiazol-2-yloxy)- 3-methoxyphenyl]-1,1,1-trifluoropropan-2-ol 174

4-[4-(1,3-benzothiazol-2-yloxy)- 3-chlorophenyl]butan-2-one 175

4-[4-(1,3-benzothiazol-2-yloxy)- 3-chlorophenyl]-1,1,1-trifluoro-2-methylbutan-2-ol 176

1-(4-{[4-(methylsulfanyl)-1,3- benzothiazol-2- yl]oxy}phenyl)ethanol 177

2-[4-(1,3-benzothiazol-2- yloxy)phenyl]propan-2-ol 178

1-[4-(1,3-benzothiazol-2- yloxy)phenyl]-2,2,2-trifluoro-N-methylethanamine 179

1-{4-[(4,6-difluoro-1,3- benzothiazol-2-yl)oxy]phenyl}-2,2,2-trifluoroethanol 180

1-{4-[(4,6-difluoro-1,3- benzothiazol-2- yl)oxy]phenyl}ethanol 181

2-{4-[(4,6-difluoro-1,3- benzothiazol-2-yl)oxy]phenyl}-1,1,1-trifluoropropan-2-ol 182

1-{4-[(1,3-benzothiazol-2- yl}oxy]-2-methoxyphenyl}-2,2,2-trifluoroethan-1-ol 183

1,1,1-trifluoro-2-methyl-4-[4- (quinolin-2- ylmethoxy)phenyl]butan-2-ol184

1,1,1-trifluoro-4-[3-methoxy-4- (quinolin-2-ylmethoxy)phenyl]-2-methylbutan-2-ol 185

1-[4-(quinolin-2-ylmethoxy)- phenyl]-3-(trifluoromethyl)- pentan-3-ol186

1-[4-(1,3-benzothiazol-2-yloxy)- 3-(cyclopentyloxy)- phenyl]pentan-3-ol187

1-[4-(1,3-benzothiazol-2-yloxy)- 3-(cyclopropylmethoxy)-phenyl]-pentan-3-ol 188

1-[4-(1,3-benzothiazol-2-yloxy)- 3-methoxyphenyl]-3-(4-methylpiperazinyl-1yl)pentane 189

4-{4-[(quinolinyl-2- yl)methoxy]phenyl}butan-2-one 190

4-{4-[(quinoline-2- yl)methoxy]phenyl}butan-2- pyrrolidine 191

1-(3-methoxy-4-{[4- (methylsulfanyl)-1,3- benzothiazol-2-yl]oxy}phenyl)pentan-3-methyl- 3-ol 192

1-(3-methoxy-4-{[4- (methylsulfanyl)-1,3- benzothiazol-2-yl]oxy}phenyl)pentan-3-one 193

1-(3-methoxy-4-{[4- (methylsulfanyl)-1,3- benzothiazol-2-yl]oxy}phenyl)pentan-3-ol 194

1-(4-{[4-(methylsulfanyl)-1,3- benzothiazol-2-yl]oxy}phenyl)pentan-3-one 195

1-(4-{[4-(methylsulfanyl)-1,3- benzothiazol-2-yl]oxy}phenyl)-3-(trifluoromethyl)pentan-3-ol 196

1-[4-(1,3-benzothiazol-2-yloxy)- 3-methoxyphenyl]pentan-3-ol 197

1,1,1-trifluoro-2-[4-(quinolin-2- ylmethoxy)phenyl]propan-2-ol 198

1,1,1-trifluoro-2-[3-methoxy-4- (quinolin-2- ylmethoxy)phenyl]butan-3-ol199

1,1,1-trifluoro-2-[3-methoxy-4- (quinolin-2-ylmethoxy)phenyl]propan-2-ol

In embodiments, the present disclosure provides the compounds in Table1, listed singly or in any combination, as well as a pharmaceuticallyacceptable enantiomer, diastereomer, salt, or solvate thereof.

In addition, the present disclosure provides compounds of formula (I) asdescribed above and in the following exemplary numbered embodiments:

-   -   1) A compound of formula (1)

-   -   -   or a pharmaceutically acceptable enantiomer, diastereomer,            salt, or solvate thereof, wherein:        -   Ar is a 9- or 10-membered bicyclic aromatic ring system,            where Ar is optionally substituted with one, two or three            substituents;        -   L is selected from a direct bond and methylene;        -   R¹ is selected from hydrogen, halide, C₁-C₆alkyl,            C₁-C₆haloalkyl, C₁-C₆alkoxy, C₃-C₆cycloalkoxy and            C₁-C₆alkoxy substituted with C₃-C₆cycloalkyl;        -   A is selected from a direct bond, —CH₂— and —CH₂CH₂—;        -   E is selected from —C(O)—R², C(OR³)R⁴R⁵ and CH(R⁶)NR⁷R⁸;        -   R² is selected from methyl, ethyl and phenyl;        -   R³ is selected from H, alkyl and substituted alkyl;        -   R⁴ is selected from hydrogen, alkyl and phenyl;        -   R⁵ is selected from C₁-C₇alkyl, C₁-C₇haloalkyl, phenyl and            substituted phenyl;        -   R⁶ is selected from hydrogen, methyl, halogenated methyl and            ethyl;        -   R⁷ is hydrogen; and R⁸ is hydrogen, methyl or ethyl; with            the proviso that together, R⁷ and R⁸ may form a 5 or            6-membered, optionally substituted, heterocycle.

    -   2) The compound of embodiment 1, or a pharmaceutically        acceptable enantiomer, diastereomer, salt, or solvate thereof,        wherein:        -   Ar is a 9- or 10-membered bicyclic ring system comprising            two aromatic rings, where Ar is unsubstituted or is            substituted with one substituent selected from halide,            C₁₋₆alkyl; —S—C₁₋₆alkyl; —O—C₁₋₆alkyl; and —SO₂—C₁₋₆alkyl;        -   L is selected from a direct bond and —CH₂— (methylene);        -   R¹ is selected from hydrogen, halide, C₁-C₆alkyl,            C₁-C₆haloalkyl and C₁-C₆alkoxy;        -   A is selected from a direct bond, —CH₂— and —CH₂CH₂—;        -   E is selected from —C(O)—R², C(OR³)R⁴R⁵ and CH(R⁶)NR⁷R⁸;        -   R² is selected from methyl, ethyl and phenyl;        -   R³ is H;        -   R⁴ is selected from hydrogen, C₁-C₇alkyl and phenyl;        -   R⁵ is selected from C₁-C₇alkyl, C₁-C₇haloalkyl, phenyl and            halophenyl;        -   R⁶ is selected from hydrogen, methyl, halogenated methyl and            ethyl; and        -   R⁷ is hydrogen and R⁸ is hydrogen, methyl or ethyl; or R⁷            and R⁸ together form a 5- or 6-membered heterocycle which is            optionally substituted with a substituent selected from            C₁-C₆alkyl and carboxylic acid.

    -   3) The compound of embodiments 1 or 2 wherein Ar is        1,3-benzothiazole.

    -   4) The compound of embodiments 1 or 2 wherein Ar is selected        from 1,3-benzoxazole and quinoline.

    -   5) The compound of embodiments 1 or 2 wherein Ar is substituted        with a single substituent which is —S—CH₃.

    -   6) The compound of embodiments 1 or 2 wherein L is a direct        bond.

    -   7) The compound of embodiments 1 or 2 wherein L is methylene.

    -   8) The compound of embodiments 1 or 2 wherein R¹ is hydrogen or        C₁-C₆alkoxy.

    -   9) The compound of embodiments 1 or 2 wherein A is a direct        bond.

    -   10) The compound of embodiments 1 ort wherein A is —CH₂CH₂—.

    -   11) The compound of embodiments 1 or 2 wherein E is —C(OR³)R⁴R⁵.

    -   12) The compound of embodiments 1 or 2 as a non-racemic mixture        of enantiomers of compounds of formula (1).

    -   13) The compound of embodiments 1 or 2 selected from:        -   1-[4-(1,3-benzothiazol-2-yloxy)-3-methoxyphenyl]-3-(trifluoromethyl)pentan-3-ol;        -   1-{3-methoxy-4-[(4-methylsulfanyl-1,3-benzothiazol-2-yl)oxy]phenyl}-3-(trifluoromethyl)pentan-3-ol;        -   1-{4-[(4,6-difluoro-1,3-benzothiazol-2-yl)oxy]-3-methoxyphenyl}-3-(trifluoromethyl)pentan-3-ol;        -   1-{4-[(6-fluoro-1,3-benzothiazol-2-yl)oxy]-3-methoxyphenyl}-3-(trifluoromethyl)pentan-3-ol;        -   4-[4-(1,3-benzothiazol-2-yloxy)-3-methoxyphenyl]-1,1,1-trifluoro-2-methylbutan-2-ol;        -   1,1,1-trifluoro-4-(3-methoxy-4-{[4-(methylsulfanyl)-1,3-benzothiazol-2-yl]oxy}phenyl)-2-methylbutan-2-ol;        -   1,1,1-trifluoro-2-{4-[(2-methyl-1,3-benzothiazol-6-yl)oxy]phenyl}propan-2-ol;        -   1,1,1-trifluoro-2-methyl-4-[4-(quinolin-2-ylmethoxy)phenyl]butan-2-ol;        -   1,1,1-trifluoro-4-[3-methoxy-4-(quinolin-2-ylmethoxy)phenyl]-2-methylbutan-2-ol;        -   1-[4-(quinolin-2-ylmethoxy)-phenyl]-3-(trifluoromethyl)-pentan-3-ol;        -   1-(3-methoxy-4-{[4-(methylsulfanyl)-1,3-benzothiazol-2-yl]oxy}phenyl)pentan-3-ol;            and        -   1-(4-{[4-(methylsulfanyl)-1,3-benzothiazol-2-yl]oxy}phenyl)-3-(trifluoromethyl)pentan-3-ol.

In addition to the above-listed compounds, the present disclosure alsoprovides the following exemplary numbered embodiments directed topharmaceutical compositions and therapeutic methods of use of thecompounds.

-   -   14) A pharmaceutical composition comprising a compound of        embodiments 1 or 2, or a pharmaceutically acceptable enantiomer,        salt or solvate thereof, and at least one pharmaceutically        acceptable carrier, diluent, excipient and/or adjuvant.    -   15) The pharmaceutical composition of embodiment 14 in a form of        an eye drop.    -   16) A method of treating an inflammatory disease or inflammatory        condition comprising administrating to a subject in need thereof        an effective amount of a compound of embodiments 1 or 2, or a        composition of embodiments 14 or 15.    -   17) The method of embodiment 16 wherein the inflammatory disease        or inflammatory condition is an ocular inflammatory disease or        an ocular inflammatory condition, respectively.    -   18) A method of treating a respiratory disease or condition        comprising administering to a subject in need thereof a        therapeutically-effective amount of a compound of embodiments 1        or 2, or a composition of embodiment 14.    -   19) A method of treating a neurodegenerative disease, condition        or disorder comprising administering to a subject in need        thereof a therapeutically-effective amount of a compound of        embodiments 1 or 2, or a composition of embodiment 14.

As mentioned above, the compounds and compositions of the presentdisclosure as set forth above, e.g., compounds of formula (1), may beused in therapeutic methods. The therapeutic method may provide either atherapeutically effective amount of the compound/composition, or aprophylactically-effective amount of the compound/composition. Forinstance, when a patient will be undergoing surgery, a compound of thedisclosure may be administered pre-surgery to minimize post-surgerytrauma. The following are exemplary therapeutic methods where thecompounds and compositions may be used.

In one aspect, the present disclosure provides a method of treatinginflammation comprising administering to a subject in need thereof atherapeutically-effective amount of a compound as set forth above.

In another aspect, the present disclosure provides a method of treatinginflammation prophylactically comprising administering to a subject inneed thereof a prophylactically-effective amount of a compound as setforth above. For example, in conditions such as asthma and allergy, thecompounds as set forth herein may be administered prophylactically toprevent exacerbation or flare of the condition.

In one aspect, the present disclosure provides a method of treating arespiratory disease or condition, comprising administering to a subjectin need thereof a therapeutically-effective amount of a compound as setforth above.

In another aspect, the present disclosure provides a method of treatingasthma comprising administering to a subject in need thereof atherapeutically-effective amount of a compound as set forth above. Inone embodiment, the subject being treated has mild to moderate asthma.In another embodiment, the subject being treated has severe asthma.

In another aspect, the present disclosure provides a method of treatingasthma comprising administering to a subject in need thereof aprophylactically-effective amount of a compound as set forth above. Inone embodiment, the subject being treated has mild to moderate asthma.In another embodiment, the subject being treated has severe asthma.

In another aspect, the present disclosure provides a method of treatingallergic disease including but not limited to dermal and ocularindications comprising administering to a subject in need thereof atherapeutically-effective amount of a compound as set forth above.

In another aspect, the present disclosure provides a method of treatingallergic disease including but not limited to dermal and ocularindications comprising administering to a subject in need thereof aprophylactically-effective amount of a compound as set forth above.

In another aspect, the present disclosure provides a method of treatingconjunctivitis. For example, the present disclosure provides a method oftreating allergic conjunctivitis comprising administering to a subjectin need thereof a therapeutically-effective amount of a compound as setforth above. Instead of allergic conjunctivitis, the conjunctivitis maybe secondary to an infection such as a viral or bacterial infection. Asanother alternative, the conjunctivitis may be caused by contact lensuse.

In another aspect, the present disclosure provides a method of treatingconjunctivitis. For example, the present disclosure provides a method oftreating allergic conjunctivitis comprising administering to a subjectin need thereof a prophylactically-effective amount of a compound as setforth above. Instead of allergic conjunctivitis, the conjunctivitis maybe secondary to an infection such as a viral or bacterial infection. Asanother alternative, the conjunctivitis may be caused by contact lensuse.

In another aspect, the present disclosure provides a method of treatinguveitis comprising administering to a subject in need thereof atherapeutically-effective amount of a compound as set forth above. Thesubject may have, for example, anterior, intermediate, posterior or panuveitis.

In another aspect, the present disclosure provides a method of treatinguveitis comprising administering to a subject in need thereof aprophylactically-effective amount of a compound as set forth above. Thesubject may have, for example, anterior, intermediate, posterior or panuveitis.

In another aspect, the present disclosure provides a method of treatingatopic dermatitis comprising administering to a subject in need thereofa therapeutically-effective amount of a compound as set forth above.

In another aspect, the present disclosure provides a method of treatingatopic dermatitis comprising administering to a subject in need thereofa prophylactically-effective amount of a compound as set forth above.

In another aspect, the present disclosure provides a method of treatingpsoriasis comprising administering to a subject in need thereof atherapeutically-effective amount of a compound as set forth above.

In another aspect, the present disclosure provides a method of treatingpsoriasis comprising administering to a subject in need thereof aprophylactically-effective amount of a compound as set forth above.

In another aspect, the present disclosure provides a method of treatingacne vulgaris comprising administering to a subject in need thereof atherapeutically-effective amount of a compound as set forth above.

In another aspect, the present disclosure provides a method of treatingacne vulgaris comprising administering to a subject in need thereof aprophylactically-effective amount of a compound as set forth above.

In another aspect, the present disclosure provides a method of treatingtendinopathy comprising administering to a subject in need thereof atherapeutically-effective amount of a compound as set forth above.

In another aspect, the present disclosure provides a method of treatingtendinopathy comprising administering to a subject in need thereof aprophylactically-effective amount of a compound as set forth above.

In another aspect, the present disclosure provides a method of treatingbronchopulmonary dysplasia comprising administering to a subject in needthereof a therapeutically-effective amount of a compound as set forthabove.

In another aspect, the present disclosure provides a method of treatingbronchopulmonary dysplasia comprising administering to a subject in needthereof a prophylactically-effective amount of a compound as set forthabove.

In another aspect, the present disclosure provides a method of treatingchronic obstructive pulmonary disease (COPD) comprising administering toa subject in need thereof a therapeutically-effective amount of acompound as set forth above. The subject may have, for example, earlystage or mild/moderate COPD.

In another aspect, the present disclosure provides a method of treatingchronic obstructive pulmonary disease (COPD) comprising administering toa subject in need thereof a prophylactically-effective amount of acompound as set forth above. The subject may have, for example, earlystage or mild/moderate COPD.

In another aspect, the present disclosure provides a method of treatinglung dysfunction comprising administering to a subject in need thereof atherapeutically-effective amount of a compound as set forth above. Thesubject may have, for example, occupational lung dysfunction related toenvironmental pollutants/hazards.

In another aspect, the present disclosure provides a method of treatinglung dysfunction comprising administering to a subject in need thereof aprophylactically-effective amount of a compound as set forth above. Thesubject may have, for example, occupational lung dysfunction related toenvironmental pollutants/hazards.

In another aspect, the present disclosure provides a method of treatingpulmonary hypertension (e.g., neonatal) comprising administering to asubject in need thereof a therapeutically-effective amount of a compoundas set forth above.

In another aspect, the present disclosure provides a method of treatingpulmonary hypertension (e.g., neonatal) comprising administering to asubject in need thereof a prophylactically-effective amount of acompound as set forth above.

In another aspect, the present disclosure provides a method of treatingcancer comprising administering to a subject in need thereof atherapeutically-effective amount of a compound as set forth above. Anexemplary cancer is a solid tumor. The cancer may be, for example breastcancer or ovarian cancer. The method may provide presentation ofmetastases of an existing cancer.

In another aspect, the present disclosure provides a method of treatingneuroinflammatory disease comprising administering to a subject in needthereof a therapeutically-effective amount of a compound as set forthabove.

In another aspect, the present disclosure provides a method of treatingneuroinflammatory disease comprising administering to a subject in needthereof a prophylactically-effective amount of a compound as set forthabove.

In one aspect, the present disclosure provides a method of treating aneurodegenerative disease, condition or disorder, comprisingadministering to a subject in need thereof a therapeutically-effectiveamount of a compound as set forth above.

In another aspect, the present disclosure provides a method of treatingmultiple sclerosis comprising administering to a subject in need thereofa therapeutically-effective amount of a compound as set forth above.

In another aspect, the present disclosure provides a method of treatingmultiple sclerosis comprising administering to a subject in need thereofa prophylactically-effective amount of a compound as set forth above.

In another aspect, the present disclosure provides a method of treatingcystic fibrosis comprising administering to a subject in need thereof atherapeutically-effective amount of a compound as set forth above. Thecystic fibrosis may be related to lung inflammation (e.g., be at anon-infectious stage).

In another aspect, the present disclosure provides a method of treatingcystic fibrosis comprising administering to a subject in need thereof aprophylactically-effective amount of a compound as set forth above. Thecystic fibrosis may be related to lung inflammation (e.g., be at anon-infectious stage).

In another aspect, the present disclosure provides a method of treatingidiopathic pulmonary fibrosis (IPF) comprising administering to asubject in need thereof a therapeutically-effective amount of a compoundas set forth above.

In another aspect, the present disclosure provides a method of treatingidiopathic pulmonary fibrosis (IPF) comprising administering to asubject in need thereof a prophylactically-effective amount of acompound as set forth above.

In another aspect, the present disclosure provides a method of treatingAlzheimer's disease, particularly early stage Alzheimer's disease,comprising administering to a subject in need thereof atherapeutically-effective amount of a compound as set forth above.

In another aspect, the present disclosure provides a method of treatingSjogren-Larsson-Syndrome comprising administering to a subject in needthereof a therapeutically-effective amount of a compound as set forthabove.

In another aspect, the present disclosure provides a method of treatingcardiovascular (CV) disease, e.g., ACS or plaque formation, comprisingadministering to a subject in need thereof a therapeutically-effectiveamount of a compound as set forth above. The population being treatedmay have an ischemia/reperfusion injury.

In another aspect, the present disclosure provides a method of treatingotitis comprising administering to a subject in need thereof atherapeutically-effective amount of a compound as set forth above. Theotitis may be, for example, secondary to an infection.

In another aspect, the present disclosure provides a method of treatinginflammation that is associated with ocular surgery comprisingadministering to a subject in need thereof a therapeutically-effectiveamount of a compound as set forth above.

In another aspect, the present disclosure provides a method of treatinginflammation that is associated with ocular surgery comprisingadministering to a subject in need thereof a prophylactically-effectiveamount of a compound as set forth above.

In another aspect, the present disclosure provides a method of treatingdry eye, comprising administering to a subject in need thereof atherapeutically effective amount of a compound as set forth above.

In another aspect, the present disclosure provides a method of treatinginflammation associated with cataract surgery comprising administeringto a subject in need thereof a therapeutically-effective amount of acompound as set forth above.

In another aspect, the present disclosure provides a method of treatinginflammation associated with cataract surgery comprising administeringto a subject in need thereof a prophylactically-effective amount of acompound as set forth above.

In another aspect, the present disclosure provides a method of treatingarthritis comprising administering to a subject in need thereof atherapeutically-effective amount of a compound as set forth above. Thearthritis may be, for example, at the early onset stage.

In another aspect, the present disclosure provides a method of treatingarthritis comprising administering to a subject in need thereof aprophylactically-effective amount of a compound as set forth above. Thearthritis may be, for example, at the early onset stage.

In another aspect, the present disclosure provides a method of treatinginflammation associated with laser eye surgery comprising administeringto a subject in need thereof a therapeutically-effective amount of acompound as set forth above.

In another aspect, the present disclosure provides a method of treatinginflammation associated with laser eye surgery comprising administeringto a subject in need thereof a prophylactically-effective amount of acompound as set forth above.

In another aspect, the present disclosure provides a method of treatingallograft rejection comprising administering to a subject in needthereof a therapeutically-effective amount of a compound as set forthabove.

In another aspect, the present disclosure provides a method of treatingallograft rejection comprising administering to a subject in needthereof a prophylactically-effective amount of a compound as set forthabove.

In another aspect, the present disclosure provides a method of treatingtrauma, e.g., a cerebral ischemia, comprising administering to a subjectin need thereof a therapeutically-effective amount of a compound as setforth above.

In another aspect, the present disclosure provides a method of treatingdiabetic retinopathy comprising administering to a subject in needthereof a therapeutically-effective amount of a compound as set forthabove.

In another aspect, the present disclosure provides a method of treatingage-related macular degeneration comprising administering to a subjectin need thereof a therapeutically-effective amount of a compound as setforth above.

In another aspect, the present disclosure provides a method of treatingdiabetic macular edema comprising administering to a subject in needthereof a therapeutically-effective amount of a compound as set forthabove.

As mentioned elsewhere herein, the present disclosure providescomposition that may be used to treat the above-mentioned medicalcondition. Those compositions may optionally include one or more activeagents other than compounds of formula (1), which, e.g., supplement,augment or complement the activity of a compound of formula (1).

In one aspect, the present disclosure provides pharmaceuticalcompositions comprising a compound of formula (1). In other words, thecompounds of the present disclosure may be formulated into apharmaceutical composition. In one aspect, the present disclosureprovides a pharmaceutical composition comprising a compound of formula(1) as set forth above, and at least one pharmaceutically acceptablecarrier, excipient or diluent.

Compounds of the disclosure can be formulated for administration for usein human or veterinary medicine, by analogy with other bioactive agentssuch as anti-inflammatory agents. Such methods are known in the art andinclude administration by any route known in the art, such as subdermal,by-inhalation, oral, topical or parenteral. Likewise, the compositionsmay be administered in intravenous (bolus or infusion), intraperitoneal,topical (e.g., ocular, eye drop), subcutaneous, intramuscular ortransdermal (e.g., patch) form, all using forms well known to those ofordinary skill in the pharmaceutical arts.

The composition is formulated into a form suitable for the desired routeof administration. In other words, a form of the compositions isselected, in part, based on the desired route of administration. Thecompositions may be in any form known in the art, including but notlimited to tablets, capsules, powders, granules, lozenges, creams orliquid preparations. A brief summary includes oral administration, whichis readily accomplished with solid (e.g., tablet, capsule, gel-cap,powder, granule, lozenge, delayed-release solid form, slow or sustainedrelease solid form, encapsulated solid form) or liquid (e.g., liquid gelcap, suspension, solution, syrup, elixir, liposomal solution)compositions. As another example, for administration by inhalation, thecomposition may be in liquid (e.g., nebulized solution/suspension) orsolid (e.g., metered dose inhaler, dry powder inhaler) form. As yetanother example, the composition may be delivered via an implant, whereexamples are an ocular implant (e.g., a slow or sustained release depotsolid form matrix) and a subcutaneous implant (e.g., a slow or sustainedrelease depot pump). When intravenous administration is deemedappropriate by the health care provider, the composition may be a liquid(e.g., solution, nano-suspension, liposomal suspension, micellarsuspension) or a solid (e.g., a lyophilized product) which may bereconstituted to provide a liquid form. When Intramuscular is thedesired route of administration, the composition may be a liquid (e.g.,solution, nano-suspension, liposomal suspension, micellar suspension,oil-based formulation) or a solid (e.g., a lyophilized product) whichmay be reconstituted to provide a liquid form. Intramuscularadministration may also be accomplished with a suitably positionedimplant. The composition may be administered subcutaneously, in whichcase the same forms that are suitable for intramuscular administrationmay be used for subcutaneous administration. Intraperitonealadministration may be used to deliver a compound or composition of thepresent disclosure, where a suitable form intraperitoneal administrationis liquid (e.g., solution, nano-suspension, liposomal suspension,micellar suspension) or solid (Lyophilized product for reconstitution).Intrathecal is another suitable route of administration, in which casethe formulation may be a liquid (e.g., solution, nano-suspension,liposomal suspension, micellar suspension) or solid (e.g., lyophilizedproduct for reconstitution). The composition may be administeredtopically to the skin of the subject, where suitable forms are liquid(e.g., solution, suspension, emulsion, cream, gel, ointment—withcarriers). Topical administration may also be for delivery to the eye ofthe subject, where suitable forms are liquid (e.g., solution,suspension, liposomal suspension, emulsion, ointment) or solid (e.g.,coated implant, implant pump). For transdermal delivery, the compoundsof the disclosure may be formulated into a transdermal patch, which mayprovide slow or sustained release of the compound to the subject. Rectaladministration may be accomplished with a suppository, such as asolid/solid wax or solid oil-based; or solid/semi-solid wax oil basedwith semi-solid liquid or gel composition. The present disclosure alsoprovides lyophilized preparations for reconstitution with a suitablevehicle. Lyophilization refers to the removal of liquid components of aformulation to provide a solid phase. Lyophilization may be accomplishedby techniques known in the art, e.g., placing the composition undervacuum and moderate heating to evaporate the liquid components. Thus,the active ingredients will typically be administered in admixture withcarrier materials selected with a view to the intended form ofadministration, such as oral tablets, capsules (either solid-filled,semi-solid filled or liquid filled), powders for constitution, oralgels, elixirs, dispersible granules, syrups, liquids, solutions andsuspensions including sterile solutions or suspensions for topicaladministration. In one embodiment the composition is administered to aneye of the subject, and the composition may take the form of a liquidcomposition that may be dropped onto the surface of the eye. Each ofsuch compositions may be made in a manner consistent with conventionalpharmaceutical practices.

In one embodiment the composition is a solid form preparation. Forexample, for oral administration the composition may be in the form oftablets, dispersible granules, and capsules. In these compositions theactive drug component may be combined with any oral non-toxicpharmaceutically acceptable inert carrier. Examples include saccharidessuch as lactose, mannitol, sucrose and other sugars, starches andcellulose; and inorganic compounds such as calcium sulfate, magnesiumstearate and dicalcium phosphate. As another example, the solid may beformulated as a suppository. For preparing suppositories, a low meltingwax such as a mixture of fatty acid glycerides or cocoa butter is firstmelted, and the active ingredient is dispersed homogeneously therein asby stirring. The molten homogeneous mixture is then poured intoconvenient sized molds, allowed to cool and thereby solidify.

Other components that may be included in the solid formulation includeconventional binders, lubricants, disintegrating agents and coloringagents. Suitable binders include starches, gelatin, natural sugars, cornsweeteners, natural and synthetic gums such as acacia, sodium alginate,carboxymethylcellulose, polyethylene glycol and waxes. Among thelubricants there may be mentioned for use in these dosage forms, boricacid, sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrants include starches, methylcellulose, guar gum, and the like.Sweetening and flavoring agents and preservatives may also be includedwhere appropriate for a dosage form intended for oral administration.Conventional excipients may be included in the composition, such asbinding agents, for example acacia, gelatin, sorbitol, tragacanth, orpolyvinylpyrollidone; fillers, for example lactose, sugar, maize-starch,calcium phosphate, sorbitol or glycine; tableting lubricants, forexample magnesium stearate, talc, polyethylene glycol or silica,disintegrants, for example potato starch; or acceptable wetting agentssuch as sodium lauryl sulphate.

The solid form preparation may contain from between about 0.5 to about100 weight percent of active ingredient including a compound of formula(1).

The compounds of the present disclosure may be formulated into a liquidpharmaceutical compositions. Liquid form preparations include solutions,suspensions and emulsions. Liquid compositions include at least onematerial that is a liquid at room temperature, where water is one suchmaterial. Other liquid materials that may be included in the liquidcomposition include propylene glycol parenteral injection. Depending onthe formulation, liquid compositions may be administered orally,topically, parenterally, intravenously and intranasally, to name a few.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives, such as suspending agents, for example sorbitol,methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose,carboxymethyl cellulose, aluminium stearate gel or hydrogenated ediblefats, emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample almond oil, oily esters such as glycerin, propylene glycol, orethyl alcohol; preservatives, for example methyl or propylp-hydroxybenzoate or sorbic acid, and, if desired, conventionalflavoring or coloring agents.

The liquid form of the pharmaceutical composition may be formulated withthe intent that the compositions will be delivered by topicaladministration, e.g., as an eyedrop. The eyedrop formulation mayoptionally contain one or more of cyclodextrin, methyl cellulose andEDTA in addition to a compound of formula (1), which may be present inthe eyedrop at a concentration of between about 0.1% to 1% (weightbasis) in the eyedrop solution. The eyedrop formulation may optionallycontain hydroxypropyl-beta-cyclodextrin in a range of 1% to 40% andhydroxypropyl methyl cellulose in a range of 0.1% to 1%. In exemplaryembodiments, the eye drop formulation may optionally contain 10%, 20%,or 30% by weight of hydroxypropyl-beta-cyclodextrin. The amount, timingand mode of delivery of compounds the disclosure will be routinelyadjusted on an individual basis, depending on such factors as weight,age, gender, and condition of the individual, the condition beinginduced or treated, whether the administration is prophylactic ortherapeutic, and on the basis of other factors known to effect drugdelivery, absorption, pharmacokinetics, including half-life, andefficacy. In exemplary embodiments, the suitable ocular dose range foruse is from about 0.01 mg to 1000 mg per day, or from 0.05 mg to about1000 mg per day, about 0.1 mg to about 1000 mg a day, about 0.5 mg toabout 1000 mg a day, about 2 mg to about 1000 mg a day, about 0.05 mg toabout 500 mg per day, 0.10 mg to 300 mg per day, 0.10 mg to 100 mg perday, 75 mg to 450 mg per day, 150 mg to 400 mg per day, about 300 mg toabout 1500 mg per day, about 600 to about 1500 mg per day. A topicaldose is typically between 0.5 mg and 3 mg/day where a dose of 3 mg/daymay be administered in the form of six applications of 0.5 mg each. Atypical oral dose is between 100 mg and 3500 mg×2 per day.

For parenteral administration, fluid unit dosage forms are preparedutilizing the compound and a sterile vehicle, water being typical. Thecompound of formula (1), depending on the vehicle and concentrationused, can be either suspended or dissolved in the vehicle or othersuitable solvent. In preparing solutions, the compound can be dissolvedin water for injection and filter sterilized before filling into asuitable vial or ampoule and sealing. To enhance the stability, thecomposition can be frozen after filling into the vial and the waterremoved under vacuum. The dry lyophilized powder is then sealed in thevial and an accompanying vial of water for injection may be supplied toreconstitute the liquid prior to use. Parenteral suspensions areprepared in substantially the same manner except that the compound issuspended in the vehicle instead of being dissolved and sterilizationcannot be accomplished by filtration. A surfactant or wetting agent isincluded in the composition to facilitate uniform distribution of thecompound. Parenteral solutions and suspensions may be used for topicaladministration.

The liquid form preparation may contain from between about 0.05 to about95 weight percent of active ingredient including a compound of formula(1).

The pharmaceutical compositions of the present disclosure include solidform preparations which are intended to be converted, shortly beforeuse, to liquid form preparations for either oral or parenteraladministration. Such liquid forms include solutions, suspensions andemulsions.

Additionally, the compositions of the present disclosure may beformulated in a sustained release form to provide a rate controlledrelease of any one or more of the components or active ingredients tooptimize therapeutic effects. Suitable dosage forms for sustainedrelease include layered tablets containing layers of varyingdisintegration rates or controlled release polymeric matricesimpregnated with the active components and shaped in tablet form orcapsules containing such impregnated or encapsulated porous polymericmatrices.

In one embodiment, the one or more Compounds of Formula (1) areadministered orally.

In another embodiment, the one or more Compounds of Formula (1) areadministered topically.

In one embodiment, a pharmaceutical preparation comprising at least onecompound of formula (1) is in unit dosage form. In such form, thepreparation is subdivided into unit doses containing effective amountsof the active components.

Compositions can be prepared according to conventional mixing,granulating or coating methods, respectively, and the presentcompositions can contain, in one embodiment, from about 0.5 wt % toabout 95 wt % of one or more compounds of formula (1). In variousembodiments, the present compositions can contain, in one embodiment,from about 1% to about 70% or from about 5% to about 60% of the compoundof formula (1).

The compounds of Formula I may be administered orally in a dosage rangeof 0.001 to 150 mg/kg of mammal (e.g., human) body weight per day in asingle dose or in divided doses. One preferred dosage range is 0.01 to100 mg/kg body weight per day orally in a single dose or in divideddoses. Another preferred dosage range is 0.1 to 50 mg/kg body weight perday orally in single or divided doses. For oral administration, thecompositions can be provided in the form of tablets or capsulescontaining 1.0 to 500 milligrams of the active ingredient, particularly1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, and 500milligrams of the active ingredient for the symptomatic adjustment ofthe dosage to the subject to be treated. The specific dose level andfrequency of dosage for any particular subject may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

The compounds of Formula I may be administered to the eye in the form ofeye drops as dosage range of 0.01 to 50 mg per day in a single dose orin divided doses in the form of one or more eye drops as a solution of0.1% to 2% by weight of compound. One preferred dosage range is 0.1 to10 mg per day in a single dose or in divided doses in the form of one ormore eye drops as a solution of 0.1% to 2% by weight of compound.Another preferred dosage range is 0.3 to 3 mg per day in a single doseor in divided doses in the form of one or more eye drops as a solutionof 0.1% to 2% by weight of compound. The compositions can be provided inthe form of eye drops containing 0.01 to 3 milligrams of the activeingredient, particularly 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7,0.8, 0.9, 1, 1.5, 2, and 3 milligrams of the active ingredient per eyedrop for the symptomatic adjustment of the dosage to the subject to betreated. The specific dose level and frequency of dosage for anyparticular subject may be varied and will depend upon a variety offactors including the activity of the specific compound employed, themetabolic stability and duration of action of that compound, the age,body weight, general health, sex, diet, mode and time of administration,rate of excretion, drug combination, the severity of the particularcondition, and the host undergoing therapy.

For convenience, the total daily dosage may be divided and administeredin portions during the day if desired. In one embodiment, the dailydosage is administered in one portion. In another embodiment, the totaldaily dosage is administered in two divided doses over a 24 hour period.In another embodiment, the total daily dosage is administered in threedivided doses over a 24 hour period. In still another embodiment, thetotal daily dosage is administered in four divided doses over a 24 hourperiod.

The amount and frequency of administration of the compounds of Formula(1) will be regulated according to the judgment of the attendingclinician considering such factors as age, condition and size of thesubject as well as severity of the symptoms being treated. Thecompositions of the disclosure can further comprise one or moreadditional therapeutic agents.

The compositions including one or more compounds of formula (1) mayinclude additional active agents. The additional active agent may, forexample, augment the biological activity of a compound of formula (1),or it may complement that activity, or it may supplement that biologicalactivity.

The compounds of formula (1) may be prepared in a number of differentways from known or readily prepared starting materials. In describingsuitable synthetic methodology, it is helpful to identify the Ar groupof formula (1) as Ar1, and the central benzene ring of formula (1) asAr2, as shown below.

Several exemplary methods for preparing representative compounds offormula (1) are illustrated in the following Schemes and Examples.Alternative synthetic pathways and analogous structures useful inpreparing compounds of formula (1) will be apparent to those skilled inthe art of organic chemical synthesis. In some cases the final productmay be further manipulated, for example, by manipulation ofsubstituents. These manipulations may include, but are not limited to,reduction, oxidation, alkylation, acylation, and hydrolysis reactionswhich are well known to those of ordinary skill in the art and arediscussed further later herein.

One factor that may be considered when preparing a compound of formula(1) is the identity of the group that links together the Ar1 and Ar2groups. That linking group is represented in formula (1) by —L—O— whereO is oxygen and L is selected from a direct bond and methylene (i.e.,—CH₂—). Thus, the linking group may take the form of 0 or CH₂O.

These linking groups may be formed by reacting together appropriatelysubstituted Ar1 and Ar2 containing compounds under suitable reactionconditions. For example, compounds of formula (1) where L is CH₂ may beprepared as shown in Scheme 1, where phenol or a R₁-substituted phenol(either of which is represented by hydroxyl substituted Ar2) is reactedwith an X-substituted benzyl compound (having the Ar1 group) where X isa leaving group. This reaction may be conducted in the presence of asuitable base such as potassium carbonate in combination with sodiumiodide, and in the presence of a suitable solvent such as acetone.

In Scheme 1, Ar1 is shown as a benzene ring, however that is forillustrative purposes only. In the compounds of the present disclosure,Ar1 is more generally identified as Ar, and represents a 9- or10-membered bicyclic aromatic ring system which is optionallysubstituted with one, two or three substituents. For example, Ar1 may bequinoline (introduced via 2(chloromethyl)quinoline hydrochloride as thealkylating agent), naphthylene (introduced via2(chloromethyl)naphthylene as the alkylating agent) or benzothiazole(introduced via 2(chloromethyl)benzothiazole as the alkylating agent, aswell as many other choices. Also in Scheme 1, Ar2 is shown assubstituted with (A/E) where this designation is meant to denotecollectively e-A—E as identified herein, and precursors thereto whichcan be converted to an A—E group after the Ar1 and Ar2 rings are coupledtogether.

When the linking group —L—O— has Las a direct bond, then the linkinggroup is oxygen (O). Such compounds may be prepared as illustrated inScheme 2.

In Scheme 2, Ar1 is illustrated as a benzothiazole compound having aleaving group X at the 2-position, however other Ar1 groups may be usedin this synthesis in lieu of benzothiazole. A few examples are2-chlorobenzoxazole, 2-chloroquinoline and 3-chloroisoquinoline. Also inScheme 2, Ar2 is shown as substituted with (A/E) where this designationis meant to denote collectively —A—E as identified herein, andprecursors thereto which can be converted to an A—E group after the Ar1and Ar2 rings are coupled together. The Ar1- and Ar2-containingcompounds may be combined under suitable reaction conditions, e.g., inthe presence of a suitable base such as potassium carbonate, and in asuitable solvent such as dimethylformamide, to provide the correspondingcoupled compound of Formula (1).

In Scheme 2, Ar2 comprises a hydroxyl group while Ar1 comprises aleaving group X. Alternatively, compounds of the present disclosure maybe prepared by a process wherein the relative placement of the hydroxylgroup and the leaving group is switched between Ar1 and Ar2 as shown inScheme 3. In Scheme 3, a phenolic compound comprising Ar1 is reactedwith a fluoroaryl compound comprising Ar2 under suitable reactionconditions, such as in the presence of a suitable base such as potassiumcarbonate and in the presence of a suitable solvent such asdimethylsulfoxide, to provide compounds of formula (1). The processoutlined in Scheme 3

In Scheme 3, Ar1 is shown as a benzene ring, however that is forillustrative purposes only. In compounds of the present disclosure, Ar1is more generally identified as Ar, and represents a 9- or 10-memberedbicyclic aromatic ring system that is optionally substituted with one,two or three substituents. Also in Scheme 3, Ar2 is shown as substitutedwith (A/E) where this designation is meant to denote collectively —A—Eas identified herein, and precursors thereto which can be converted toan A—E group after the Ar1 and Ar2 rings are coupled together. Thereaction outlined in Scheme 3 is favored when A/E is an electronwithdrawing group, e.g., carbonyl, in which case the (A/E) substituentsin (F)(R¹)Ar2(A/E) is a precursor to —A—E.

The compounds of the present disclosure may have a variety ofsubstituents on the Ar1 and Ar2 moieties. These substituents may beprepared by standard methodology known in the art. Such methodologyincludes benzylation, condensation, hydrogenolysis, O-alkylation,Grignard reaction, trifluoromethylation, reduction, reductive aminationof aromatic/aliphatic ketones, reductive amination of aliphatic ketones,and reductive amination of aromatic ketones, any one or more of whichmay optionally be used in the preparation of compounds of formula (1).These techniques may also be modified according to the knowledge ofthose skilled in the art. The following provides General Procedures thatare further exemplified in the specific Examples which follow.

Benzylation: Phenolic compound (1 eq), benzyl bromide (1.5 eq) and K₂CO₃(1.5 eq) in acetone are stirred at reflux for 3-18 h. The reactionmixture is allowed to cool to room temperature and filtered. The filtercake is washed with acetone, and the solvent is removed under reducedpressure. The material is purified by flash chromatography.

Condensation: To a stirred solution of aldehyde (1 eq) in MeOH/H₂O isadded ketone (4 to 8 eq), followed by 85% by weight KOH (4 to 6 eq). Themixture is stirred at room temperature for 7 days or at reflux for 3 h.The reaction is quenched with 1-5% aq. HCl or water and extracted withEtOAc. The organic layer is washed with water, dried (MgSO₄), filtered,and the solvent is removed under reduced pressure. The material ispurified by trituration with ether/hexane or by flash chromatography.

Hydrogenolysis: A mixture of unsaturated ketone (1 eq) and 10% Pd/C (10%by weight) in methanol or ethyl acetate (with or without catalyticamount of acetic acid) is stirred under hydrogen for 1 to 18 h. Thereaction is filtered, and the solvent is removed under reduced pressure.The material is purified by flash chromatography.

O-alkylation: Phenolic compound (1 eq), alkylating agent (1 to 1.5 eq),K₂CO₃ (1 to 1.5 eq), and dimethylformamide (DMF) are heated under argonto 90-150° C. for approximately 16-24 hours and cooled to roomtemperature. The reaction is diluted with water and ethyl acetate. Theorganic layer is washed with 5% aqueous sodium hydroxide and/or water,washed with brine, dried (MgSO₄), filtered, and the solvent is removedunder reduced pressure. The material is purified using flash columnchromatography.

Grignard reaction: Grignard reactions can be carried out usingcommercially available alkyl or aryl magnesium bromides or preparedfreshly as follows. (1) Preparation of Grignard Reagent. To freshlycrushed magnesium turnings (2.5 to 5.0 eq) under argon in THF (1.5 mmolof Mg per mL of tetrahydrofuran (THF)) is added 1,2 dibromoethane (50μL) and stirred for 5 minutes and followed by ethyl magnesium bromide(50 μL, 3.0M in ether) and stirred for another 5 min. Alkyl or arylbromide (1 eq) is then added and the reaction is cooled occasionallywith a water bath over 1 hr. (2) Grignard Additions. To a 0° C. solutionof ketone (1 eq) as a solution in dry THF under argon is added Grignardreagent (generally 1 to 2 eq). The reaction is stirred for approximately1 hr. and quenched with water and/or 5% aqueous HCl. The mixture isextracted with water, washed with brine, dried (MgSO₄), filtered, andthe solvent is removed under reduced pressure. The material is purifiedusing flash column chromatography.

Trifluoromethylation: To a solution of ketone (1 eq) in dry DMF at roomtemperature or reduced temperature (e.g. 0° C.) is added CF₃-TMS (1.5 to2 eq) followed by a catalytic amount of K₂CO₃ (^(˜)0.1 to 0.3 eq) andstirred under argon for a desired length of time, typically 18-72 hours.The reaction is diluted with water and washed with brine. The organiclayer is dried (MgSO₄), filtered, and the solvent removed in vacuo. Tothe residue in methanol is added conc. HCl, and the solution is stirreduntil the reaction is complete (^(˜)1 hr). The reaction is diluted withethyl acetate and extracted with brine. The organic layer is dried(MgSO₄), filtered, and the solvent removed under reduced pressure. Thematerial is purified using flash column chromatography.

Reduction: To a solution of ketone (1 eq) in methanol under argon isadded sodium borohydride (2 eq) and stirred for 1 h. Optionally, cerium(III) chloride heptahydrate (1 eq) may be added. The reaction is dilutedwith water and 5% aqueous HCl and extracted once with ethyl acetate. Theorganic layer is washed with brine, dried (MgSO₄), filtered, and thesolvent is removed under reduced pressure. The material is purifiedusing flash column chromatography.

Reductive amination of aromatic/aliphatic ketones: To a stirred solutionof aromatic or aliphatic ketone (1 eq) in THF at room temperature underargon is added Ti(OiPr)₄ (1.2 eq), followed by amine (1.4 eq). Thereaction mixture is stirred at reflux for ^(˜)18 h, and then is allowedto cool to room temperature. NaBH₄ (1.5 eq) is added, and the reactionmixture is stirred for 1 to 3 h. It is then quenched with water andextracted three times with ethyl acetate (EtOAc). The organic layer iswashed with water, dried (MgSO₄), filtered, and the solvent is removedunder reduced pressure. The material is purified by flashchromatography.

Reductive amination of aliphatic ketones: To a stirred solution ofaliphatic ketone (1 eq) in DCE at room temperature under argon is addedamine (1.2 eq), followed by NaBH(OAc)₃ (2 eq) and acetic acid (AcOH, 2eq) optionally with 4A molecular sieves. The reaction mixture is stirredfor 18 h, quenched with water, and extracted three times with eitherCH₂Cl₂ or EtOAc. The organic layer is dried (MgSO₄), filtered, and thesolvent is removed under reduced pressure. The material is purified byflash chromatography.

Reductive amination of aromatic aldehydes: To a stirred solution ofaromatic aldehyde (1 eq) in DCE at room temperature under argon is addedamine (1.2 eq), followed by NaBH(OAc)₃ (1.5 eq). The reaction mixture isstirred for 18 h, quenched with water, and extracted three times witheither CH₂Cl₂ or EtOAC. The organic layer is dried (MgSO₄), filtered,and the solvent is removed under reduced pressure. The material ispurified by flash chromatography.

Reductive amination to form primary and secondary alkyl amines: To astirred mixture of NH₄Cl (1 eq) in methanol (MeOH) at room temperatureunder argon are added Et₃N (1 eq), ketone (1 eq), and Ti(OiPr)₄ (^(˜)2eq). The reaction mixture is stirred for 18 h. Another 1 equivalent ofEt₃N and NH₄Cl may be added and the reaction mixture then stirred for 3h. NaBH₄ (1.2 eq) is added, and the reaction mixture is stirred for 1.5h. Another portion of NaBH₄ (0.5 eq) may optionally be added, and thereaction mixture is stirred for 1 h. It is quenched with water andextracted with EtOAc. The organic layer is washed with water, dried overanhydrous MgSO₄, filtered, and the solvent is removed under reducedpressure. The residue is purified by flash chromatography.

Reductive amination and trifluoromethylation: To a stirred solution ofketone or aldehyde (1 eq) in THF under argon at room temperature isadded 4A molecular sieves and ethylamine (˜6 eq). The mixture is stirredunder argon at room temperature for 3 h, filtered, and the solvent isremoved under reduced pressure. To the residue is added KHF₂ (^(˜)0.75eq), acetonitrile and DMF and the mixture is cooled to at 0° C. underargon. TFA (^(˜)1.3 eq) is added. The mixture is stirred for 5 minutes,and then CF₃TMS (^(˜)1.5 eq) is added. The cooling bath is removed, andthe reaction mixture is stirred for ^(˜)18 hours, diluted with saturatedaqueous Na₂CO₃ and extracted with EtOAc. The organic layer is washedwith water, dried over anhydrous MgSO₄, filtered, and the solvent isremoved under reduced pressure. The residue is purified by flashchromatography. To the residue is added MeOH then NaBH₄ (0.67 eq), andthe mixture is stirred under argon for 30 minutes. The reaction isquenched with water and extracted with EtOAc. The organic layer is driedover anhydrous Na₂SO₄, filtered, and the solvent is removed underreduced pressure. The residue is purified by flash chromatography.

In each case standard reactions may be monitored by thin layerchromatography (TLC) to determine progress of reaction. Temperatureand/or reaction time may be increased or decreased to increase theconversion of starting material to product or to reduce formation ofby-products.

The Examples and preparations provided below further illustrate andexemplify the compounds of the present disclosure and methods ofpreparing such compounds. It is to be understood that the scope of thepresent invention is not limited in any way by the scope of thefollowing Examples and preparations. The starting materials and variousreactants utilized or referenced in the examples may be obtained fromcommercial sources, or are readily prepared from commercially availableorganic compounds, using methods well-known to one skilled in the art.

In the following Examples, standard abbreviations are used including thefollowing: AcOH=acetic acid; aq.=aqueous; BnBr=benzyl bromide;CF₃TMS=TMSCF₃=CF₃—Si(CH₃)₃; Conc.=concentrated; DCE=1,2-dichloroethane;DMF=N,N-dimethylformamide; DMSO—dimethylsulfoxide;dppp=1,3-Bis(diphenylphosphino)propane; EtOAc=ethyl acetate;Et₂O=diethyl ether; h=hour; Hex=hexanes; MeCN=acetonitrile;MeOH=methanol; mL=milliliters; TBS=tert-butyl dimethyl silyl;TBSCI=tert-butyl dimethyl silyl chloride; TFA=trifluoroacetic acid,i.e., CF₃—COOH; TLC=thin layer chromatography; wt %=percentage byweight, e.g., 5% EtOAc in Hex refers to 5 weight parts (e.g., grams)ethyl acetate in combination with 95 weight parts (e.g., grams) hexanes.

In the following Examples, molecules with a single chiral center, unlessotherwise noted, exist as a racemic mixture. Those molecules with two ormore chiral centers, unless otherwise noted, exist as a racemic mixtureof diastereomers. Single enantiomers/diastereomers may be obtained bymethods known to those skilled in the art. For example, enantiomers maybe separated from one another by HPLC using a chiral column such as aChiralPak™ column (Daicel Corp., Japan), e.g., ChiralPak AD™ which has asize of 4.6×250 mm and contains particles having an average diameter of5 μm. The mobile phase may be a mixture of iso-propanol in hexane, wherethe i-PrOH/hexane ratio may be varied to impact the degree of separationof the enantiomers. An exemplary flow rate is 1 mL/min and an exemplaryinjection volume is 50 μL, working with a sample concentration of 5mg/mL. The run time may likewise be adjusted to enhance separation,where an exemplary run time is 11 minutes.

For selected compounds prepared according to the following examples, ¹HNMR (nuclear magnetic resonance spectroscopy) was performed to obtain ¹HNMR spectra, which are characterized as provided in Table 6, whichfollows these Examples.

EXAMPLES Example 1 Preparation of Compound 101

To a stirred solution of 4-hydroxy-3-methoxybenzaldehyde (10 g, 65.8mmol) in MeOH (85 mL)/H₂O (13 mL) was added 2-butanone (50 mL, 556 mmol)followed by KOH (15 g, 214 mmol). The mixture was stirred at roomtemperature for 7 days. The reaction was quenched with the addition ofwater and aq. HCl (15 mL conc. HCl in 200 mL water) and extracted withEtOAc (300 mL). The organic layer was washed with water (2×150 mL),dried over anhydrous MgSO₄, filtered, and the solvent was removed underreduced pressure. The residue was triturated with Et₂O/Hex (1:3),filtered and washed with Et₂O/Hex (1:3) to yield 5.2 g of1-(4-hydroxy-3-methoxyphenyl)pent-1-en-3-one as a yellow solid.

To a stirred solution of 1-(4-hydroxy-3-methoxyphenyl)pent-1-en-3-one(5.0 g, 24 mmol) in MeOH (75 mL) was added 10% Pd/C (250 mg). Thereaction mixture was stirred under hydrogen for 1 h after which time anadditional 10% Pd/C (250 mg) was added. Stirring under hydrogen wascontinued for an additional 2 h, and then the mixture was filtered. Thesolvent was removed under reduced pressure, and the residue was purifiedby flash chromatography (25% EtOAc in Hex) to yield 2.45 g of1-(4-hydroxy-3-methoxyphenyl)pentan-3-one as a colourless oil.

A mixture of 1-(4-hydroxy-3-methoxyphenyl)pentan-3-one (1.5 g, 7.20mmol), K₂CO₃ (1.00 g, 7.24 mmol), and 2-chlorobenzothiazole (1.00 mL,7.68 mmol) in DMF (15 mL) was stirred under argon at 100° C. for 18 h.The mixture was allowed to cool to room temperature, diluted with EtOAc(30 mL), washed with water (30 mL), brine (2×30 mL), dried overanhydrous MgSO₄, filtered, and the solvent was removed under reducedpressure. The residue was purified by flash chromatography (25% EtOAc inHex) to yield 2.10 g of Compound 101 as a yellow solid.

Example 2 Preparation of Compound 102

A mixture of 1-(4-hydroxy-3-methoxyphenyl)pentan-3-one (170 mg, 0.82mmol, prepared as described in Example 1), K₂CO₃ (130 mg, 0.94 mmol),and 2-chlorobenzoxazole (1004, 0.87 mmol) in DMF (3 mL) was stirred in asealed tube at 83° C. for 16 h. The mixture was allowed to cool to roomtemperature and water (10 mL), brine (10 mL) and EtOAc (20 mL) wereadded. The layers were separated, the aqueous layer extracted with EtOAc(10 mL) and the combined organic layers were washed with brine (10 mL),dried over anhydrous MgSO₄, filtered, and the solvent was removed underreduced pressure. The residue was purified by flash chromatography (30%EtOAc in Hex) to yield 130 mg of Compound 102 as an oil.

Example 3 Preparation of Compound 103

To a stirred mixture of Compound 101 (1.50 g, 3.98 mmol) and K₂CO₃ (60mg, 0.434 mmol) in DMF (20 mL) under argon was added CF₃TMS (1.30 mL,8.80 mmol). The reaction mixture was stirred for 18 h at roomtemperature, and then was diluted with EtOAc (40 mL) and water (10 mL)and washed with brine (3×40 mL). The organic layer was dried overanhydrous MgSO₄, filtered, and the solvent was removed under reducedpressure. The residue was taken-up in MeOH (20 mL), combined with conc.HCl (2 mL) and stirred for 1 h. The solvent was removed under reducedpressure, the residue was taken-up in EtOAc (40 mL) and washed withwater (2×40 mL) then brine (40 mL). The organic layer was dried overanhydrous MgSO₄, filtered, and the solvent was removed under reducedpressure. The residue was purified by flash chromatography (25% EtOAc inHex) to yield 1.54 g of Compound 103 as a yellow oil.

Example 4 Preparation of Compound 104

To a stirred mixture of 1-(4-hydroxy-3-methoxyphenyl)pentan-3-one (843mg, 4.05 mmol, prepared as in Example 1) and K₂CO₃ (56 mg, 0.405 mmol)in DMF (8 mL) cooled in an ice bath to 0° C. under argon was addedCF₃TMS (1.50 mL, 10.2 mmol) dropwise. The cooling bath was removed andthe reaction mixture was stirred at room temperature for 18 h. Themixture was diluted with EtOAc (40 mL) and washed with water (2×25 mL).The organic layer was dried over anhydrous MgSO₄, filtered, and thesolvent was removed under reduced pressure. The residue was taken-up inMeOH (8 mL) and stirred with conc. HCl (0.6 mL) for 1 h. The mixture wasdiluted with EtOAc (40 mL) and washed with water (2×25 mL). The organiclayer was dried over anhydrous MgSO₄, filtered, and the solvent wasremoved under reduced pressure. The residue was purified by flashchromatography (30% EtOAc in Hex) to yield 938 mg of4-[3-hydroxy-3-(trifluoromethyl)pentyl]-2-methoxyphenol as a yellow oil.

A mixture of 4-[3-hydroxy-3-(trifluoromethyl)pentyl]-2-methoxyphenol(150 mg, 0.539 mmol), K₂CO₃ (223 mg, 1.61 mmol), and2-chloro-4-(methylthio)-benzothiazole (145 mg, 0.672 mmol) in DMF (3 mL)was stirred in a sealed tube at 100° C. for 18 h. The mixture wasallowed to cool to room temperature, diluted with EtOAc (35 mL), washedwith water (2×25 mL), dried over anhydrous MgSO₄, filtered, and thesolvent was removed under reduced pressure. The residue was purified byflash chromatography (20% EtOAc in Hex) to yield 230 mg of Compound 104as a yellow oil, which solidified at room temperature.

The two enantiomers of Compound 104 were separated from one another byHPLC using the following conditions: column: ChiralPak AD™, 5 μmparticle size, 4.6×250 mm; mobile phase: 20% i-PrOH in hexane; flowrate: 1 mL/min; injection volume: 50 μL; sample concentration: 5 mg/mL;run time: 11 minutes; number of injections: 16. Each peak was manuallycollected, the fractions containing each enantiomer were combined, andthe solvent was removed under reduced pressure to give 2 mg of eachenantiomer.

Each set of combined fractions was examined for purity by HPLC at 1mg/mL using the same column, mobile phase, and run time as mentionedabove. Enantiomer 1 had a retention time of 7.633 min, and >99% purity.¹H NMR for enantiomer 1 (400 MHz, CDCl₃): δ 7.44-7.39 (m, 1H), 7.26 (d,1H), 7.21 (d, 1H), 7.20 (s, 1H), 6.89-6.82 (m, 2H), 3.82 (s, 3H), 2.76(t, 2H), 2.55 (s, 3H), 2.07-1.99 (m, 2H), 1.90-1.80 (m, 2H), 1.06 (t,3H). Enantiomer 2 had a retention time of 9.368 min, and >99% purity. ¹HNMR for enantiomer 2 (400 MHz, CDCl₃): δ 7.43-7.39 (m, 1H), 7.26 (d,1H), 7.21 (d, 1H), 7.20 (s, 1H), 6.89-6.82 (m, 2H), 3.82 (s, 3H), 2.76(t, 2H), 2.55 (s, 3H), 2.07-1.99 (m, 2H), 1.89-1.78 (m, 2H), 1.06 (t,3H).

Example 5 Preparation of Compound 105

Following the procedure of Example 4 for making Compound 104 exceptusing 2-chloro-1-methyl-1H-1,3-benzodiazole (112 mg, 0.672 mmol) insteadof 2-chloro-4-(methylthio)-benzothiazole and stirring at 150° C. for 64h yielded 112 mg of Compound 105 as a white solid.

The two enantiomers of Compound 105 were separated from one another byHPLC using the following conditions: ChiralPak AD™ column, 5 μm particlesize, 4.6×250 mm column dimensions; mobile phase: 90% i-PrOH in hexane;flow rate: 1 mL/min; injection volume: 50 μL; sample concentration: 1mg/mL; run time: 17 minutes; number of injections: 1. Each peak wasmanually collected to provide two fractions. 50 μL samples from eachfraction were separately re-injected into the HPLC column. Enantiomer 1had a retention time of 13.975 min and >99% purity. Enantiomer 2 had aretention time of 15.487 min and >99% purity.

Example 6 Preparation of Compound 106

Following the procedure of Example 4 for making Compound 104 exceptusing 2-chloro-6-(methylsulfonyl)benzothiazole (167 mg, 0.674 mmol)instead of 2-chloro-4-(methylthio)-benzothiazole yielded 145 mg ofCompound 106 as a yellowish oil, which solidified at room temperature.

Example 7 Preparation of Compound 107

Following the procedure of Example 4 for preparing Compound 104 exceptusing 2-chloro-4,6-difluorobenzothiazole (138 mg, 0.671 mmol) instead of2-chloro-4-(methylthio)-benzothiazole yielded 231 mg of Compound 107 asa colourless oil.

Example 8 Preparation of Compound 108

A mixture of 4-[3-hydroxy-3-(trifluoromethyl)pentyl]-2-methoxyphenolprepared as in Example 4 (124 mg, 0.45 mmol), K₂CO₃ (100 mg, 0.71 mmol),and 2-chloro-6-fluoro-benzothiazole (166 mg, 0.88 mmol) in DMF (2.5 mL)was stirred in a sealed tube at 100° C. for 18 h. The mixture wasallowed to cool to room temperature, diluted with EtOAc (15 mL) and H₂O(15 mL). The layers were separated and the aqueous layer was extractedwith EtOAc (20 mL). The organic layers were combined and washed withbrine, dried over anhydrous MgSO₄, filtered, and the solvent was removedunder reduced pressure. The residue was purified by flash chromatography(20% EtOAc in Hex) to yield 83 mg of Compound 108 as an oil.

Example 9 Preparation of Compound 109

A mixture of 4-[3-hydroxy-3-(trifluoromethyl)pentyl]-2-methoxyphenolprepared as in Example 4 (124 mg, 0.45 mmol), K₂CO₃ (87 mg, 0.62 mmol),and 2-chloro-6-methoxy-benzothiazole (180 mg, 0.90 mmol) in DMF (2.5 mL)was stirred in a sealed tube at 100° C. for 18 h. The mixture wasallowed to cool to room temperature, then diluted with EtOAc (15 mL) andH₂O (15 mL). The layers were separated and the aqueous layer wasextracted with EtOAc (20 mL). The organic layers were combined andwashed with brine, dried over anhydrous MgSO₄, filtered, and the solventwas removed under reduced pressure. The residue was purified by flashchromatography (20% EtOAc in Hex) to yield 118 mg of Compound 109 as acolourless oil.

Example 10 Preparation of Compound 110

To a solution of vanillyl acetone (15, 250 mg, 1.29 mmol) in DMF (3 mL)under argon was added 2-chlorobenzothiazole (168 μl, 1.29 mmol) andK₂CO₃ (267 mg, 1.93 mmol). The reaction mixture was stirred in a sealedtube at 100° C. for 18 hours. The reaction mixture was diluted withwater and ethyl acetate. The organic layer was then washed with 5%aqueous sodium hydroxide, water, and brine. The organic layer was dried(MgSO₄), filtered, and the solvent was removed under reduced pressure.Flash column chromatography on silica gel (30% EtOAc in Hex) yielded 321mg of Compound 110 as a white solid.

Example 11 Preparation of Compound 111

To a stirred mixture of Compound 110 (150 mg, 0.458 mmol) and K₂CO₃ (6mg, 0.043 mmol) in DMF (2 mL) at 0° C. under argon was added CF₃TMS (135μL, 0.914 mmol) dropwise. The cooling bath was removed and the reactionmixture was stirred at room temperature for 18 h. The mixture wasdiluted with EtOAc (35 mL) and washed with water (25 mL). The organiclayer was dried over anhydrous Na₂SO₄, filtered, and the solvent wasremoved under reduced pressure. The residue was taken-up in MeOH (3 mL),combined with conc. HCl (0.3 mL) and stirred for 1 h. The mixture wasdiluted with EtOAc (35 mL) and washed with water (25 mL). The organiclayer was dried over anhydrous Na₂SO₄, filtered, and the solvent wasremoved under reduced pressure. The residue was purified by flashchromatography (20% EtOAc in Hex) to yield 100 mg of Compound 111 as acolourless oil.

Example 12 Preparation of Compound 112

3,4-Dihydroxybenzaldehyde (0.50 g, 3.62 mmol), benzyl bromide (0.43 mL,3.62 mmol), K₂CO₃ (0.75 g, 5.43 mmol), NaI (0.054 g, 0.36 mmol), andacetone (10 mL) were combined, stirred under argon and brought toreflux. The reaction mixture was stirred at reflux for 18 hours,filtered and concentrated. The residue was purified by flash columnchromatography on silica gel (20% EtOAc in Hex) to yield 483 mg of4-(benzyloxy)-3-hydroxybenzaldehyde as a white solid.

To a stirred solution of 4-(benzyloxy)-3-hydroxybenzaldehyde (1.50 g,6.57 mmol) in MeOH (14 mL)/H₂O (1.4 mL) KOH (1.73 g, 26.2 mmol) wasadded followed by 2-butanone (5.3 mL, 58.80 mmol). The mixture wasstirred at reflux for 2 h. The reaction was allowed to cool to roomtemperature then quenched with 10% aq. HCl (60 mL) and extracted withEtOAc (2×50 mL). The organic layer was washed with water (2×150 mL),dried over anhydrous MgSO₄, filtered, and the solvent was removed underreduced pressure. The residue was triturated with diethyl ether to yield0.648 g of 1-[4-(benzyloxy)-3-hydroxyphenyl]pent-1-en-3-one as anoff-white solid.

A mixture of 1-[4-(benzyloxy)-3-hydroxyphenyl]pent-1-en-3-one (0.5 g,1.77 mmol), K₂CO₃ (0.734 g, 5.31 mmol), and 2-bromopropane (0.830 mL,8.84 mmol) in DMF (5 mL) was stirred in a sealed tube at 90° C. for 18h. The mixture was allowed to cool to room temperature, diluted withEtOAc (35 mL), washed with water (3×25 mL), dried over anhydrous MgSO₄,filtered, and the solvent was removed under reduced pressure to yield0.531 g of 1-[4-(benzyloxy)-3-(propan-2-yloxy)phenyl]pent-1-en-3-one asan off-white solid.

To a stirred solution of1-[4-(benzyloxy)-3-(propan-2-yloxy)phenyl]pent-1-en-3-one (0.400 g, 1.23mmol) in EtOAc (12 mL) and AcOH (600 μL) 10% Pd/C (0.040 g) was added.The reaction mixture was stirred under hydrogen for 5 h and thenfiltered. The solvent was removed under reduced pressure, and theresidue was purified by flash chromatography (30% EtOAc in Hex) to yield0.193 g of 1-[4-(hydroxy)-3-(propan-2-yloxy)phenyl]pentan-3-one.

A mixture of 1-[4-(hydroxy)-3-(propan-2-yloxy)phenyl]pentan-3-one (236mg, 1.00 mmol), K₂CO₃ (140 mg, 1.01 mmol), and 2-chlorobenzothiazole(0.145 mL, 1.1 mmol) in DMF (3 mL) was stirred in a sealed tube at 100°C. for 18 h. The mixture was allowed to cool to room temperature,diluted with EtOAc (35 mL), washed with water (2×25 mL), dried overanhydrous MgSO₄, filtered, and the solvent was removed under reducedpressure. The residue was purified by flash chromatography (20% EtOAc inHex) to yield 245 mg of Compound 112 as a yellow oil.

Example 13 Preparation of Compound 113

A mixture of 1-[4-(benzyloxy)-3-hydroxyphenyl]pent-1-en-3-one (0.5 g,1.77 mmol, prepared as in Example 12), K₂CO₃ (0.367 g, 2.66 mmol), andcyclopentylbromide (0.290 mL, 2.70 mmol) in DMF (5 mL) was stirred in asealed tube at 90° C. for 18 h. The mixture was allowed to cool to roomtemperature, diluted with EtOAc (35 mL), washed with water (3×25 mL),dried over anhydrous MgSO₄, filtered, and the solvent was removed underreduced pressure. The residue was triturated with ether/Hex to yield0.454 g of 1-[4-(benzyloxy)-3-(cyclopentyloxy)phenyl]pent-1-en-3-one asan off-white solid.

To a stirred solution of1-[4-(benzyloxy)-3-(cyclopentyloxy)phenyl]pent-1-en-3-one (0.450 g, 1.28mmol) in EtOAc (14 mL) and AcOH (700 μL) 10% Pd/C (0.045 g) was added.The reaction mixture was stirred under hydrogen for 23 h and thenfiltered. The solvent was removed under reduced pressure, and theresidue was purified by flash chromatography (30% EtOAc in Hex) to yield0.193 g of 1-[4-(hydroxy)-3-(cyclopentyloxy)phenyl]pentan-3-one.

A mixture of 1-[4-(hydroxy)-3-(cyclopentyloxy)phenyl]pentan-3-one (0.234mg, 0.892 mmol), K₂CO₃ (0.124 g, 0.897 mmol), and 2-chlorobenzothiazole(0.130 mL, 0.998 mmol) in DMF (3 mL) was stirred in a sealed tube at100° C. for 18 h. The mixture was allowed to cool to room temperature,diluted with EtOAc (35 mL), washed with water (2×25 mL), dried overanhydrous MgSO₄, filtered, and the solvent was removed under reducedpressure. The residue was purified by flash chromatography (20% EtOAc inHex) to yield 0.245 g of Compound 113 as a yellow oil.

Example 14 Preparation of Compound 114

A mixture of 1-[4-(benzyloxy)-3-hydroxyphenyl]pent-1-en-3-one (0.5 g,1.77 mmol, prepared as in Example 12), K₂CO₃ (0.367 g, 2.66 mmol), and(bromomethyl)cyclopropane (0.260 mL, 2.68 mmol) in DMF (5 mL) wasstirred in a sealed tube at 90° C. for 18 h. The mixture was allowed tocool to room temperature, diluted with EtOAc (35 mL), washed with water(3×25 mL), dried over anhydrous MgSO₄, filtered, and the solvent wasremoved under reduced pressure. The residue was triturated withether/Hex to yield 0.440 g of1-[4-(benzyloxy)-3-(cyclopropylmethoxy)phenyl]pent-1-en-3-one as asolid.

To a stirred solution of1-[4-(benzyloxy)-3-(cyclopropylmethoxy)phenyl]pent-1-en-3-one (0.440 g,1.31 mmol) in EtOAc (14 mL) and AcOH (700 μL) 10% Pd/C (0.044 g) wasadded. The reaction mixture was stirred under hydrogen for 18 h and thenfiltered. The solvent was removed under reduced pressure, and theresidue was purified by flash chromatography (20% EtOAc in Hex) to yield0.244 g of 1-[4-(hydroxy)-3-(cyclopropylmethoxy)phenyl]pentan-3-one.

A mixture of 1-[4-(hydroxy)-3-(cyclopropylmethoxy)phenyl]pentan-3-one(0.244 mg, 0.983 mmol), K₂CO₃ (0.136 g, 0.984 mmol), and2-chlorobenzothiazole (0.140 mL, 1.08 mmol) in DMF (4 mL) was stirred ina sealed tube at 100° C. for 18 h. The mixture was allowed to cool toroom temperature, diluted with EtOAc (35 mL), washed with water (3×25mL), dried over anhydrous MgSO₄, filtered, and the solvent was removedunder reduced pressure. The residue was purified by flash chromatography(20% EtOAc in Hex) to yield 0.285 g of Compound 114 as a yellow oil.

Example 15 Preparation of Compound 115

To a stirred mixture of Compound 112 (235 mg, 0.636 mmol) and K₂CO₃ (9mg, 0.065 mmol) in DMF (3 mL) under argon was added CF₃TMS (0.120 mL,0.813 mmol) dropwise. The reaction mixture was stirred at roomtemperature for 18 h. The mixture was partitioned between EtOAc (35 mL)and water (25 mL) and the aqueous layer was extracted with EtOAc (35mL). The combined organic layers was dried over anhydrous MgSO₄,filtered, and concentrated. The residue was taken-up in MeOH (6 mL),conc. HCl (0.1 mL) was added and the mixture was stirred for 1 h. Themixture was diluted with EtOAc (35 mL) and washed with water (2×25 mL).The organic layer was dried over anhydrous MgSO₄, filtered, andconcentrated. The residue was purified by flash chromatography (20%EtOAc in Hex) to yield 203 mg of Compound 115 as a white solid.

Example 16 Preparation of Compound 116

To a stirred mixture of Compound 113 (0.125 g, 0.316 mmol) and K₂CO₃(0.004 g, 0.029 mmol) in DMF (1.5 mL) under argon was added CF₃TMS(0.060 mL, 0.406 mmol) dropwise. The reaction mixture was stirred atroom temperature for 18 h. The mixture was diluted with EtOAc (35 mL)and washed with water (2×25 mL). The organic layer was dried overanhydrous MgSO₄, filtered, and concentrated. The residue was taken-up inMeOH (3 mL), conc. HCl (0.05 mL) was added and the mixture was stirredfor 1 h. The mixture was diluted with EtOAc (35 mL) and washed withwater (2×25 mL). The organic layer was dried over anhydrous MgSO₄,filtered, and concentrated. The residue was purified by flashchromatography (20% EtOAc in Hex) to yield 0.106 g of Compound 116 as awhite solid.

Example 17 Preparation of Compound 117

To a stirred mixture of Compound 114 (0.150 g, 0.393 mmol) and K₂CO₃(0.006 g, 0.043 mmol) in DMF (2 mL) under argon was added CF₃TMS (0.080mL, 0.572 mmol) dropwise. The reaction mixture was stirred at roomtemperature for 18 h. The mixture was diluted with EtOAc (35 mL) andwashed with water (2×25 mL). The organic layer was dried over anhydrousMgSO₄, filtered, and concentrated. The residue was taken-up in MeOH (3mL), conc. HCl (0.05 mL) was added and the mixture was stirred for 1 h.The mixture was diluted with EtOAc (35 mL) and washed with water (2×25mL). The organic layer was dried over anhydrous MgSO₄, filtered, andconcentrated. The residue was purified by flash chromatography (20%EtOAc in Hex) to yield 0.121 g of Compound 117 as a white solid.

Example 18 Preparation of Compound 118

To a solution of vanillyl acetone (150 mg, 0.772 mmol), K₂CO₃ (160 mg,1.16 mmol), and 2-chloro-4-(methylthio)-benzothiazole (208 mg, 0.964mmol) in DMF (3 mL) was stirred in a sealed tube at 100° C. for 18 h.The mixture was allowed to cool to room temperature, diluted with EtOAc(35 mL), washed with water (2×25 mL), dried over anhydrous MgSO₄,filtered, and the solvent was removed under reduced pressure. Theresidue was purified by flash chromatography (20% EtOAc in Hex) to yield214 mg of Compound 118 as a yellow oil.

Example 19 Preparation of Compound 119

To a stirred mixture of Compound 118 (214 mg, 0.599 mmol) and K₂CO₃ (8mg, 0.058 mmol) in DMF (3 mL) under argon was added CF₃TMS (133 μL,0.901 mmol) dropwise. The mixture was stirred at room temperature for 18h. The mixture was diluted with EtOAc (35 mL) and washed with water(2×25 mL). The organic layer was dried over anhydrous MgSO₄, filtered,and the solvent was removed under reduced pressure. The residue wastaken-up in MeOH (3 mL) conc. HCl (0.3 mL) was added and the mixture wasstirred for 1 h. The mixture was diluted with EtOAc (35 mL) and washedwith water (2×25 mL). The organic layer was dried over anhydrous MgSO₄,filtered, and the solvent was removed under reduced pressure. Theresidue was purified by flash chromatography (20% EtOAc in Hex) to yield95 mg of Compound 119 as a yellow oil.

Example 20 Preparation of Compound 120

To a stirred solution of 3-ethoxy-4-hydroxybenzaldehyde (2 g, 12 mmol)in MeOH (17 mL)/H₂O (2.5 mL) 2-butanone (10 mL, 111 mmol) was added,followed by KOH (3 g, 45 mmol). The mixture was stirred at roomtemperature for 18 h. The reaction was quenched with 10% aq. HCl andextracted with EtOAc (3×30 mL). The organic layer was washed with brine(30 mL), dried over anhydrous MgSO₄, filtered, and the solvent wasremoved under reduced pressure. The residue was purified by flash columnchromatography (20% EtOAc in Hex) to yield 2.09 g of1-(3-ethoxy-4-hydroxyphenyl)pent-1-en-3-one as a solid.

To a stirred solution of 1-(3-ethoxy-4-hydroxyphenyl)pent-1-en-3-one(1.73 g, 7.86 mmol) in EtOAc (15 mL) 10% Pd/C (150 mg) was added. Thereaction mixture was stirred under hydrogen for 1.5 h and then wasfiltered. The solvent was removed under reduced pressure, and theresidue was purified by flash chromatography (40% EtOAc in Hex) to yield0.720 g of 1-(3-ethoxy-4-hydroxyphenyl)pentan-3-one.

A mixture of 1-(3-ethoxy-4-hydroxyphenyl)pentan-3-one (0.430 g, 1.94mmol), K₂CO₃ (0.266 g, 1.92 mmol), and 2-chlorobenzothiazole (0.277 mL,2.13 mmol) in DMF (3 mL) was stirred under argon at 120° C. for 18 h.The mixture was allowed to cool to room temperature, diluted with EtOAc(20 mL), washed with water (2×15 mL), brine (15 mL), dried overanhydrous MgSO₄, filtered, and the solvent was removed under reducedpressure. The residue was purified by flash chromatography (20% EtOAc inHex) to yield 0.492 g of Compound 120 as an oil.

Example 21 Preparation of Compound 121

To a stirred mixture of Compound 120 (0.100 g, 0.281 mmol) and K₂CO₃(0.018 g) in DMF (2 mL) under argon was added CF₃TMS (0.100 mL, 0.678mmol). The reaction mixture was stirred for 18 h at room temperature andthen was diluted with EtOAc (15 mL) and washed with brine (2×15 mL). Theorganic layer was dried over anhydrous MgSO₄, filtered, and the solventwas removed under reduced pressure. The residue was taken-up in MeOH (5mL) and stirred with conc. HCl (0.250 mL) for 1 h. The solvent wasremoved under reduced pressure, the residue was taken-up in EtOAc (20mL) and washed with brine (2×20 mL). The organic layer was dried overanhydrous MgSO₄, filtered, and the solvent was removed under reducedpressure. The residue was purified by flash chromatography (20% EtOAc inHex) to yield 72 mg of Compound 121 as a colourless oil.

Example 22 Preparation of Compound 122

Following general procedure for reductions, Compound 122 was preparedfrom Compound 110 (0.46 mmol, prepared as in Example 10), sodiumborohydride (0.91 mmol), and methanol (3 mL). Flash columnchromatography of the crude mixture on silica gel (40% EtOAc in Hex)yielded 0.156 g of Compound 122 as an oil.

Example 23 Preparation of Compound 123

Following General Procedure for Grignard Additions, Compound 123 wasprepared from Compound 110 (0.150 g, 0.46 mmol, prepared as in Example10), THF (3.0 mL), and phenyl magnesium bromide (0.30 mL, 3 M in Et₂O).Flash column chromatography of the crude mixture on silica gel (30%EtOAc in Hex) yielded 0.204 g of Compound 123 as an oil.

Example 24 Preparation of Compound 124

Following General Procedure for Grignard Additions, Compound 124 wasprepared from Compound 110 (0.100 g, 0.305 mmol, prepared as in Example10), THF (1.0 mL), and methyl magnesium bromide (0.20 mL, 3 M in Et₂O).Flash column chromatography of the crude mixture on silica gel (50-70%EtOAc in Hex) yielded 0.115 g of Compound 124 as an oil.

Example 25 Preparation of Compound 125

To a solution of vanillyl acetone (0.621 g, 3.20 mmol) in DMF (8 mL)under argon was added 2-chlorobenzoxazole (300 μL, 2.62 mmol) and K₂CO₃(0.511 g, 3.70 mmol). The reaction mixture was stirred at 140° C. for 18hours. The reaction mixture was diluted with water and EtOAc. Theorganic layer was then washed with 5% aqueous NaOH (2×30 mL) and brine(20 mL). The organic layer was dried over MgSO₄, filtered, and thesolvent was removed under reduced pressure. Flash column chromatographyon silica gel (40% EtOAc in Hex) yielded 0.483 g of Compound 125 as awhite solid.

Example 26 Preparation of Compound 126

Following General Procedure for Grignard Additions, methyl magnesiumbromide (0.180 mL, 3 M in Et₂O) was added to a flask which had beencooled in an ice-water bath and contained a stirring mixture of Compound125 (0.095 g, 0.305 mmol) in THF (3.0 mL). The ice-bath was removed andthe mixture was allowed to stir for 70 minutes at room temperature. H₂O(5 mL) was added followed by EtOAc (10 mL) and brine (5 mL). The layerswere separated and the aqueous layer was extracted with EtOAc (2×10 mL).The combined organic layers were washed with brine, dried over MgSO₄,filtered and the filtrate concentrated. Flash column chromatography ofthe crude mixture on silica gel (30% EtOAc in Hex) yielded 0.090 g ofCompound 126 as a colourless oil.

Example 27 Preparation of Compound 127

Following General Procedure for Grignard Additions, ethyl magnesiumbromide (0.180 mL, 3 M in Et₂O) was added to a flask which has beencooled in an ice-water bath and contained a stirring mixture of Compound125 (0.101 g, 0.325 mmol) in THF (3.0 mL). The ice-bath was removed andthe mixture was allowed to stir for 70 minutes at room temperature. H₂O(5 mL) was added followed by EtOAc (10 mL) and brine (5 mL). The layerswere separated and the aqueous layer was extracted with EtOAc (2×10 mL).The combined organic layers were washed with brine, dried over MgSO₄,filtered and the filtrate concentrated. Flash column chromatography ofthe crude mixture on silica gel (40% EtOAc in Hex) yielded 0.066 g ofCompound 127 as a colourless oil.

Example 28 Preparation of Compound 128

Following General Procedure for Grignard Additions, phenyl magnesiumbromide (0.180 mL, 3 M in Et₂O) was added to a flask which had beencooled in an ice-water bath and contained a stirring mixture of Compound125 (0.097 g, 0.314 mmol) in THF (3.0 mL). The ice-bath was removed andthe mixture was allowed to stir for 70 minutes at room temperature. H₂O(5 mL) was added followed by EtOAc (10 mL) and brine (5 mL). The layerswere separated and the aqueous layer was extracted with EtOAc (2×10 mL).The combined organic layers were washed with brine, dried over MgSO₄,filtered and the filtrate concentrated. Flash column chromatography ofthe crude mixture on silica gel (40% EtOAc in Hex) yielded 0.080 g ofCompound 128 as a colourless oil.

Example 29 Preparation of Compound 129

To a stirred solution of 3-ethoxy-4-hydroxybenzaldehyde (2.00 g, 12.0mmol) and 85% KOH (3.00 g, 45.4 mmol) in MeOH (17 mL)/H2O (2.5 mL),acetophenone (4.5 mL, 38.6 mmol) was added. The mixture was stirred atroom temperature while monitoring by TLC. Upon completion, standardworkup and concentration provided a residue which was carried forward tothe next step without further purification. The residue was dissolved inEtOAc (30 mL), 10% Pd/C (320 mg) was added and the mixture was stirredunder hydrogen for 1 h. The mixture was filtered and the filtrateconcentrated to yield 1.2 g of3-(3-ethoxy-4-hydroxyphenyl)-1-phenylpropan-1-one as a yellow solid.

To a solution of 3-(3-ethoxy-4-hydroxyphenyl)-1-phenylpropan-1-one (1.20g, 4.44 mmol) in DMF (8 mL) under argon was added 2-chlorobenzothiazole(682 μL, 5.26 mmol) and K₂CO₃ (0.648 g, 4.70 mmol). The reaction mixturewas stirred at 140° C. for 18 hours. The reaction mixture was dilutedwith water and ethyl acetate. The organic layer was then washed withbrine. The organic layer was dried (MgSO₄), filtered, and the solventwas removed under reduced pressure. Flash column chromatography onsilica gel (15-20% EtOAc in Hex) yielded 1.11 g of Compound 129 as anoil.

Example 30 Preparation of Compound 130

To a stirred mixture of Compound 129 (0.200 g, 0.5 mmol) and K₂CO₃(0.015 g, 0.11 mmol) in DMF (3 mL) under argon was added CF₃TMS (0.172mL, 1.16 mmol) dropwise. The reaction mixture was stirred at roomtemperature for 18 h. The mixture was diluted with EtOAc (15 mL) andwashed with brine (2×15 mL). The organic layer was concentrated and theresidue was taken-up in MeOH (5 mL) and stirred with conc. HCl (0.25 mL)for 1 h. The mixture was diluted with EtOAc (20 mL) and washed withbrine (2×20 mL). The organic layer was dried over anhydrous MgSO₄,filtered, and the solvent was removed under reduced pressure. Theresidue was purified by flash chromatography (20% EtOAc in Hex) to yield178 mg of Compound 130 as an oil.

Example 31 Preparation of Compound 131

A mixture of vanillin (2.00 g, 13.1 mmol), acetophenone (5.00 mL, 42.9mmol), and KOH (6 g, 106.5 mmol) in MeOH (20 mL)/H₂O (58 mL) in a sealedtube was warmed up to 60° C. with stirring, and stirred at 60° C. for 4h. The reaction mixture was allowed to cool to room temperature,quenched with aq. HCl (10 mL conc. HCl in 100 mL water), and extractedwith EtOAc (100 mL). The organic layer was washed with water (2×100 mL)and brine (20 mL), dried over anhydrous MgSO₄, filtered, and the solventwas removed under reduced pressure. The residue was purified by flashchromatography (15% to 40% EtOAc in Hex) to yield 3.8 g of3-(4-hydroxy-3-methoxyphenyl)-1-phenylprop-2-en-1-one.

A mixture of 3-(4-hydroxy-3-methoxyphenyl)-1-phenylprop-2-en-1-one (1.27g, 4.99 mmol), and 10% Pd/C (139 mg) in EtOAc (10 mL) and Et₃N (1.3 mL)was stirred under hydrogen for 2 h, and then was filtered. The solventwas removed under reduced pressure, and the residue was purified byflash chromatography (20% EtOAc in Hex, 30% EtOAc in Hex) to yield 311mg of 3-(4-hydroxy-3-methoxyphenyl)-1-phenylpropan-1-one.

A mixture of 3-(4-hydroxy-3-methoxyphenyl)-1-phenylpropan-1-one (768 mg,3 mmol), K₂CO₃ (414 mg, 3 mmol) and 2-chlorobenzothiazole (429 μL, 3.2mmol) in DMF (5 mL) was warmed to 100° C. with stirring, and was stirredat 100° C. for 18 h. The reaction mixture was allowed to cool to roomtemperature, diluted with EtOAc (30 mL) and washed with brine (3×30 mL),dried over anhydrous MgSO₄, filtered, and the solvent was removed underreduced pressure to yield 813 mg of Compound 131 as a white solid.

Example 32 Preparation of Compound 132

Compound 131 (100 mg, 0.257 mmol) and NaBH₄ (46 mg, 1.22 mmol) in MeOH(3 mL) was stirred at room temperature under argon for 1 h. The reactionwas quenched with EtOAc (25 ml) and 5% aq. HCl (25 mL), and the aqueouslayer was extracted with EtOAc (15 mL). The combined organic layer waswashed with brine (2×20 mL), dried over anhydrous MgSO₄, filtered, andthe solvent was removed under reduced pressure. The residue was purifiedby flash chromatography (30% EtOAc in Hex) to yield 114 mg of Compound132 as a colourless oil.

Example 33 Preparation of Compound 133

To a stirred mixture of Compound 131 (250 mg, 0.642 mmol) and K₂CO₃ (18mg, 0.130 mmol) in DMF (3 mL) under argon was added CF₃TMS (200 μL, 1.35mmol). The reaction mixture was stirred at room temperature for 24 h,and then was diluted with EtOAc (35 mL) and washed with brine (3×30 mL).The organic layer was dried over anhydrous MgSO₄, filtered, and thesolvent was removed under reduced pressure. The residue was taken-up inMeOH (10 mL) and stirred with conc. HCl (0.25 mL) for 2 h. The solventwas removed under reduced pressure, and the residue was taken-up inEtOAc (30 mL), washed with water (2×20 mL) and brine (20 mL), dried overanhydrous MgSO₄, filtered, and the solvent was removed under reducedpressure. The residue was purified by flash chromatography (20% EtOAc inHex) to yield 264 mg of Compound 133 as a yellowish oil.

Example 34 Preparation of Compound 134

To a stirred solution of Compound 131 (167 mg, 0.429 mmol) in THF (8 mL)at room temperature under argon was added Ti(OiPr)₄ (150 μL, 0.507mmol), followed by pyrrolidine (50 μL, 0.609 mmol). The reaction mixturewas stirred at reflux for 16 h, and then was allowed to cool to roomtemperature. NaBH₄ (24 mg, 0.634 mmol) was added, the reaction mixturewas stirred for 3 h, and then was quenched with water (25 mL) andextracted with EtOAc (2×35 mL). The organic layer was washed with water(35 mL), dried over anhydrous MgSO₄, filtered, and the solvent wasremoved under reduced pressure. The residue was purified by flashchromatography (EtOAc/MeOH/Et3N, 9:1:0.1) to yield 108 mg of Compound134 as a yellow foam.

Example 35 Preparation of Compound 135

To a stirred mixture of NH₄Cl (313 mg, 5.85 mmol) in MeOH (6 mL) at roomtemperature under argon were added Et₃N (820 μL, 5.88 mmol), Compound101 from Example 1 (200 mg, 0.586 mmol), and Ti(OiPr)4 (350 μL, 1.18mmol). The milk-like reaction mixture was stirred for 18 h. Et₃N (820μL) and NH₄Cl (313 mg) were added, and the reaction mixture was stirredfor 3 h. NaBH₄ (45 mg) was added, and the reaction mixture was stirredfor 1.5 h. Another portion of NaBH₄ (23 mg) was added, and the reactionmixture was stirred for 1 h. The reaction was quenched with water (35mL) and extracted with EtOAc (40 mL). The organic layer was washed withwater (2×35 mL), dried over anhydrous MgSO₄, filtered, and the solventwas removed under reduced pressure. The residue was purified by flashchromatography (10% MeOH in EtOAc, then EtOAc/MeOH/Et₃N, 9:1:0.1) toyield 62 mg of Compound 135 as a yellowish oil.

Example 36 Preparation of Compound 136

To AcOH (5.00 mL, 87.4 mmol) in toluene (70 mL) at 0° C. under argon wasadded NaBH₄ (1.00 g, 26.4 mmol), portionwise over 30 minutes. Thecooling bath was removed, and the reaction mixture was stirred for 1 h,filtered, and the insoluble material was washed with ether and dried toyield 3.19 g of NaBH(OAc)₃.

To a stirred mixture of Compound 101 (150 mg, 0.439 mmol, prepared as inExample 1) in DCE (3 mL) at room temperature under argon were added 4 Amolecular sieves powder (150 mg), AcOH (100 μL), morpholine (50 μL,0.578 mmol), and NaBH(OAc)₃ (190 mg, 0.896 mmol), prepared as describedabove. The reaction mixture was stirred for 18 h. An additional quantityof morpholine (50 μL) was added, and stirring was continued for 2 h. Thereaction mixture was quenched with saturated aqueous NaHCO₃ (25 mL) andextracted with CH₂Cl₂ (2×35 mL). The combined organic layer was driedover anhydrous MgSO₄, filtered, and the solvent was removed underreduced pressure. The residue was purified by flash chromatography(EtOAc/MeOH/Et₃N, 9:1:0.1) to yield 30 mg of a colourless oil. The oilwas taken up in CH₂Cl₂ (3 mL) and stirred with 1.25 M HCl in MeOH (100μL) for 1 h. The solvents were removed under reduced pressure to yield30 mg of the hydrochloride salt of Compound 136 as a white foam.

Example 37 Preparation of Compound 137

A mixture of vanillin (250 mg, 1.64 mmol), K₂CO₃ (341 mg, 2.47 mmol),and 2-chlorobenzothiazole (260 μL, 2.00 mmol) in DMF (5 mL) was stirredin a sealed tube at 100° C. for 18 h. The mixture was allowed to cool toroom temperature, diluted with EtOAc (35 mL), washed with water (3×25mL), dried over anhydrous MgSO₄, filtered, and the solvent was removedunder reduced pressure. The residue was purified by flash chromatography(20% EtOAc in Hex) to yield 407 mg of4-(1,3-benzothiazol-2-yloxy)-3-methoxybenzaldehyde as a white solid.

To a stirred mixture of4-(1,3-benzothiazol-2-yloxy)-3-methoxybenzaldehyde (200 mg, 0.701 mmol)and K₂CO₃ (10 mg, 0.072 mmol) in DMF (3 mL) under argon was added CF₃TMS(155 μL, 1.05 mmol). The reaction mixture was stirred at roomtemperature for 42 h, and then was diluted with EtOAc (40 mL) and washedwith water (2×25 mL). The organic layer was dried over anhydrous MgSO₄,filtered, and the solvent was removed under reduced pressure. Theresidue was taken-up in MeOH (3 mL) and stirred with conc. HCl (0.15 mL)for 1 h. The mixture was diluted with EtOAc (40 mL) and washed withwater (2×25 mL). The organic layer was dried over anhydrous MgSO₄,filtered, and the solvent was removed under reduced pressure. Theresidue was purified by flash chromatography (20% EtOAc in Hex) to yield109 mg of Compound 137 as a white solid.

Example 38 Preparation of Compound 138

To a stirred mixture of4-(1,3-benzothiazol-2-yloxy)-3-methoxybenzaldehyde (250 mg, 0.876 mmol,prepared as in Example 37) and anhydrous Na₂SO₄ (1 g) at roomtemperature under argon was added ethylamine (2.0 M solution in THF, 2.0mL, 4.0 mmol). The reaction mixture was stirred for 18 h and then wasfiltered to remove the solid. The solvent was removed under reducedpressure to yield a yellowish oil. To the oil and KHF₂ (51 mg, 0.653mmol) in MeCN (3 mL) and DMF (203 μL, 2.62 mmol) at 0° C. under argonwas added TFA (84 μL, 1.10 mmol). The mixture was stirred for 5 minutes,and CF₃TMS (194 μL, 1.31 mmol) was added. The cooling bath was removed,and the reaction mixture was stirred for 18 h. The mixture was dilutedwith saturated aq. Na₂CO₃ (40 mL) and extracted with EtOAc (40 mL). Theorganic layer was washed with water (2×25 mL), dried over anhydrousMgSO₄, filtered, and the solvent was removed under reduced pressure. Theresidue was purified by flash chromatography (15% EtOAc in Hex) to yield61 mg of Compound 138 as an off-white solid.

Example 39 Preparation of Compound 139

A mixture of vanillin (150 mg, 0.985 mmol), K₂CO₃ (204 mg, 1.48 mmol)and 2-chloro-4-(methylthio)benzothiazole (266 mg, 1.23 mmol) in DMF (3mL) was stirred in a sealed tube at 100° C. for 18 h, and then wasallowed to cool to room temperature, diluted with EtOAc (35 mL) andwashed with 1 M NaOH (2×25 mL) and water (25 mL). The organic layer wasdried over anhydrous MgSO₄, filtered, and the solvent was removed underreduced pressure. The residue was purified by flash chromatography (20%EtOAc in Hex) to yield 256 mg of3-methoxy-4-{[4-(methylsulfanyl)-1,3-benzothiazol-2-yl]oxy}benzaldehydeas a white solid.

To a stirred mixture of3-methoxy-4-{[4-(methylsulfanyl)-1,3-benzothiazol-2-yl]oxy}benzaldehyde(256 mg, 0.772 mmol) and K₂CO₃ (11 mg, 0.080 mmol) in DMF (3 mL) underargon was added CF₃TMS (171 μL, 1.16 mmol). The reaction mixture wasstirred at room temperature for 42 h, and then was diluted with EtOAc(35 mL) and washed with water (2×25 mL). The organic layer was driedover anhydrous MgSO₄, filtered, and the solvent was removed underreduced pressure. The residue was taken up in MeOH (3 mL) and stirredwith conc. HCl (0.3 mL) for 1 h. The mixture was diluted with EtOAc (35mL) and washed with water (2×25 mL). The organic layer was dried overanhydrous MgSO₄, filtered, and the solvent was removed under reducedpressure. The residue was purified by flash chromatography (20% EtOAc inHex) to yield 192 mg of Compound 139 as a yellowish solid.

Example 40 Preparation of Compound 140

To a solution of 4-(4-hydroxyphenyl)-2-butanone (1.5 g, 9.1 mmol) in DMF(8 mL) under argon was added 2-chlorobenzothiazole (1.34 mL, 10.3 mmol)and K₂CO₃ (1.27 g, 9.2 mmol). The reaction mixture was stirred at 140°C. for 20 hours. The reaction mixture was allowed to cool to roomtemperature, and then was diluted with water (20 mL) and extracted withEtOAc (3×20 mL). The organic layer was washed with 5% aqueous NaOH (2×20mL) and brine (2×2 mL). The organic layer was dried (MgSO₄), filtered,and the solvent was removed under reduced pressure. Flash columnchromatography on silica gel (30% EtOAc in Hex) yielded 1.72 g of4-[4-(1,3-benzothiazol-2-yloxy)phenyl]butan-2-one.

Following General Procedure for CF₃TMS Additions as disclosed herein,Compound 140 was prepared from4-[4-(1,3-benzothiazol-2-yloxy)phenyl]butan-2-one (135 mg, 0.45 mmol),CF₃TMS (200 μL, 1.35 mmol), K₂CO₃ (20 mg, 0.14 mmol) and DMF (3 mL).Flash column chromatography of the crude mixture on silica gel (30%EtOAc in Hex) yielded 137 mg of Compound 140 as an oil.

Example 41 Preparation of Compound 141

Following General Procedure for Reductions as disclosed herein, Compound141 was prepared from 4-[4-(1,3-benzothiazol-2-yloxy)phenyl]butan-2-one(113 mg, 0.38 mmol, prepared as in Example 40), NaBH₄ (25 mg, 0.59mmol), CeCl₃×7H₂O (125 mg, 0.34 mmol), and MeOH (3 mL). Flash columnchromatography of the crude mixture on silica gel (50% EtOAc in Hex)yielded 100 mg of Compound 141 as a colourless oil.

Example 42 Preparation of Compound 142

Following General Procedure for Grignard Additions, Compound 142 wasprepared from 4-[4-(1,3-benzothiazol-2-yloxy)phenyl]butan-2-one (128 mg,0.43 mmol, prepared as in Example 40), THF (2.0 mL), and isopropylmagnesium bromide (0.45 mL, 2 M in THF). Flash column chromatography ofthe crude mixture on silica gel (30% EtOAc in Hex) yielded 52 mg ofCompound 142 as an oil.

Example 43 Preparation of Compound 143

Following General Procedure for Grignard Additions, Compound 143 wasprepared from 4-[4-(1,3-benzothiazol-2-yloxy)phenyl]butan-2-one (195 mg,0.66 mmol, prepared as in Example 40), THF (2.0 mL), and ethyl magnesiumbromide (0.32 mL, 3 M in Et₂O). Flash column chromatography of the crudemixture on silica gel (30% EtOAc in Hex) yielded 168 mg of Compound 143.

Example 44 Preparation of Compound 144

Following General Procedure for Grignard Additions, Compound 144 wasprepared from 4-[4-(1,3-benzothiazol-2-yloxy)phenyl]butan-2-one (195 mg,0.66 mmol, prepared as in Example 40), THF (2.0 mL), and phenylmagnesium bromide (0.32 mL, 3 M in Et₂O). Flash column chromatography ofthe crude mixture on silica gel (30% EtOAc in Hex) yielded 222 mg ofCompound 144 as an oil.

Example 45 Preparation of Compound 145

Following General Procedure for Grignard Additions, Compound 145 wasprepared from 4-[4-(1,3-benzothiazol-2-yloxy)phenyl]butan-2-one (220 mg,0.74 mmol, prepared as in Example 40), THF (9.0 mL), and 4-fluorophenylmagnesium bromide (0.8 mmol). 4-Fluorophenyl magnesium bromide wasprepared following General Procedure for the Preparation of GrignardReagents using 1-bromo-4-fluorobenzene (0.8 mmol) and magnesium (2.2mmol). Flash column chromatography of the crude mixture on silica gel(30% EtOAc in Hex) yielded 323 mg of Compound 145 as a colourless oil.

Example 46 Preparation of Compound 146

To a solution of 4-(4-hydroxyphenyl)-2-butanone (518 mg, 3.2 mmol) inDMF (8 mL) under argon was added 2-chlorobenzoxazole (300 μL, 2.6 mmol)and K₂CO₃ (496 mg, 3.6 mmol). The reaction mixture was stirred at 130°C. for 15 hours. The reaction mixture was diluted with water (20 mL),brine (20 mL), and EtOAc (30 mL). The layers were separated, the aqueouslayer was extracted with EtOAc (20 mL) and the combined organic layerswere washed with brine (20 mL). The organic layer was dried (MgSO₄),filtered, and the solvent was removed under reduced pressure. Flashcolumn chromatography on silica gel (30% EtOAc in Hex) yielded 605 mg of4-[4-(1,3-benzoxazol-2-yloxy)phenyl]butan-2-one as a colourless oil.

Following General Procedure for Grignard Additions, Compound 146 wasprepared from 4-[4-(1,3-benzoxazol-2-yloxy)phenyl]butan-2-one (101 mg,0.36 mmol), THF (3.0 mL), and ethyl magnesium bromide (0.150 mL, 3 M inEt₂O). Flash column chromatography of the crude mixture on silica gel(30% EtOAc in Hex) yielded 80 mg of Compound 146.

Example 47 Preparation of Compound 147

Following General Procedure for Grignard Additions, Compound 147 wasprepared from 4-[4-(1,3-benzoxazol-2-yloxy)phenyl]butan-2-one (101 mg,0.36 mmol, prepared as in Example 46), THF (3.0 mL), and phenylmagnesium bromide (0.2 mL, 3 M in Et₂O). Flash column chromatography ofthe crude mixture on silica gel (30% EtOAc in Hex) yielded 96 mg ofCompound 83.

Example 48 Preparation of Compound 148

To a mixture of 4-hydroxybenzaldehyde (2.0 g, 16.4 mmol) in MeOH (17mL)/H₂O (2.5 mL) 2-butanone (10 mL, 111 mmol) was added, followed by KOH(3.0 g, 45.4 mmol). The mixture was stirred at room temperature for 3days. The reaction was quenched with 10% aq. HCl (15 mL) and extractedwith EtOAc (40 mL). The organic layer was washed with water (2×30 mL),then brine (1×30 mL), dried over anhydrous MgSO₄, filtered, and thesolvent was removed under reduced pressure. The residue was trituratedwith ether/Hex (40 mL, 1:1) to yield 1.29 g of1-(4-hydroxyphenyl)pent-1-en-3-one as a solid.

To a stirred solution of 1-(4-hydroxyphenyl)pent-1-en-3-one (1.25 g,7.17 mmol) in EtOAc (12 mL) 10% Pd/C (125 mg) was added. The reactionmixture was stirred under hydrogen for 1 h. The mixture was filtered andthe solvent was removed under reduced pressure. The residue was purifiedby flash chromatography (20% to 40% EtOAc in Hex) to yield 650 mg of1-(4-hydroxyphenyl)pentan-3-one.

A mixture of 1-(4-hydroxyphenyl)pentan-3-one (200 mg, 1.12 mmol), K₂CO₃(154 mg, 1.11 mmol), and 2-chlorobenzothiazole (0.160 mL, 1.23 mmol) inDMF (3 mL) was stirred in a sealed tube at 120° C. for 18 h. The mixturewas allowed to cool to room temperature, diluted with EtOAc (10 mL),washed with brine (3×10 mL), dried over anhydrous MgSO₄, filtered, andthe solvent was removed under reduced pressure. The residue was purifiedby flash chromatography (25% EtOAc in Hex) to yield 303 mg of Compound148 as an oil.

Example 49 Preparation of Compound 149

To a stirred solution of 3-chloro-4-hydroxybenzaldehyde (0.250 g, 1.60mmol) in MeOH (2 mL)/H₂O (0.32 mL) 2-butanone (0.60 mL, 6.66 mmol) wasadded, followed by KOH (0.422 g, 6.39 mmol). The mixture was stirred at75° C. for 2 hours. The reaction was allowed to cool to roomtemperature. EtOAc (35 mL) and 10% aq HCl (25 mL) were added. The layerswere separated and the organic layer was washed with water (25 mL),dried over anhydrous MgSO₄, filtered, and the solvent was removed underreduced pressure. The residue was purified by flash chromatography(10-20% EtOAc in Hex) to yield 0.290 g of1-(3-chloro-4-hydroxyphenyl)pent-1-en-3-one as a yellow oil.

To a stirred solution of 1-(3-chloro-4-hydroxyphenyl)pent-1-en-3-one(0.690 g, 1.38 mmol) in EtOAc (15 mL) 10% Pd/C (29 mg) was added. Thereaction mixture was stirred under hydrogen for 1 h. The reactionmixture was filtered. The solvent was removed under reduced pressure,and the residue was purified by flash chromatography (20% EtOAc in Hex)to yield 0.090 g of 1-(3-chloro-4-hydroxyphenyl)pentan-3-one as a yellowoil.

A mixture of 1-(3-chloro-4-hydroxyphenyl)pentan-3-one (199 mg, 0.936mmol), K₂CO₃ (194 mg, 1.40 mmol), and 2-chlorobenzothiazole (0.150 mL,1.15 mmol) in DMF (4 mL) was stirred in a sealed tube at 100° C. for 18h. The mixture was allowed to cool to room temperature, diluted withEtOAc (35 mL), washed with water (3×25 mL), dried over anhydrous MgSO₄,filtered, and the solvent was removed under reduced pressure. Theresidue was purified by flash chromatography (20% EtOAc in Hex) to yield165 mg of Compound 149 as a yellow oi

Example 50 Preparation of Compound 150

A mixture of Compound 148 (100 mg, 0.321 mmol, prepared as in Example48), K₂CO₃ (15 mg, 0.108 mmol) and CF₃TMS (0.100 mL, 0.677 mmol) in DMF(2 mL) was stirred at room temperature under argon for 18 h. The mixturewas diluted with EtOAc (415 mL) and washed with brine (2×15 mL). Theorganic layer was concentrated under reduced pressure. The residue wastaken-up in MeOH (5 mL) and stirred with conc. HCl (0.25 mL) for 1 h.The mixture was diluted with EtOAc (20 mL) and washed with brine (2×20mL). The organic layer was dried over anhydrous MgSO₄, filtered, and thesolvent was removed under reduced pressure. The residue was purified byflash chromatography (30% EtOAc in Hex) to yield 111 mg of Compound 150as an oil.

Example 51 Preparation of Compound 151

A mixture of Compound 149 (153 mg, 0.442 mmol; prepared as in Example49), K₂CO₃ (6 mg, 0.043 mmol) and CF₃TMS (0.091 mL, 0.616 mmol) in DMF(2 mL) was stirred at room temperature under argon for 18 h. The mixturewas diluted with EtOAc (35 mL) and washed with water (2×25 mL). Theorganic layer was dried over anhydrous MgSO₄, filtered, and the solventwas removed under reduced pressure. The residue was taken-up in MeOH(4.5 mL) and stirred with conc. HCl (0.07 mL) for 1 h. The mixture wasdiluted with EtOAc (35 mL) and washed with water (2×25 mL). The organiclayer was dried over anhydrous MgSO₄, filtered, and the solvent wasremoved under reduced pressure. The residue was isolated as a colourlessoil that solidified upon standing at room temperature to yield 0.093 gof Compound 151 as a white solid.

Example 52 Preparation of Compound 152

A mixture of 3-fluoro-4-hydroxybenzaldehyde (250 mg, 1.78 mmol), benzylbromide (320 μL, 2.69 mmol) and K₂CO₃ (372 mg, 2.69 mmol) in acetone (5mL) was stirred at reflux for 16 h, and then was allowed to cool to roomtemperature, filtered and washed with acetone. The filtrate wasconcentrated under reduced pressure, and the residue was purified byflash chromatography (20% EtOAc in Hex) to yield 212 mg of4-(benzyloxy)-3-fluorobenzaldehyde as a white solid.

A mixture of 4-(benzyloxy)-3-fluorobenzaldehyde (212 mg, 0.921 mmol),2-butanone (80 μL, 0.888 mmol) and 85% KOH (182 mg, 2.76 mmol) in MeOH(3 mL) and water (0.6 mL) was stirred in a sealed tube at 75° C. for 1h. The reaction was allowed to cool to room temperature and filtered.The solid was washed with water, MeOH, and dried to yield 146 mg of1-[4-(benzyloxy)-3-fluorophenyl]pent-1-en-3-one as a white solid.

1-[4-(benzyloxy)-3-fluorophenyl]pent-1-en-3-one (146 mg, 0.514 mmol) and10% Pd on C (15 mg) were combined in EtOAc (14 mL) under argon. AcOH (14drops) was added. The flask was evacuated and back-filled with hydrogen(balloon). The reaction mixture was stirred for 20 h, and then wasfiltered and washed with EtOAc. The filtrate was concentrated underreduced pressure to yield 96 mg of1-[4-(benzyloxy)-3-fluorophenyl]pentan-3-one as a white solid.

A mixture of 1-[4-(benzyloxy)-3-fluorophenyl]pentan-3-one (96 mg, 0.489mmol), K₂CO₃ (101 mg, 0.731 mmol), and 2-chlorobenzothiazole (100 μL,0.768 mmol) in DMF (2 mL) was stirred in a sealed tube at 100° C. for 16h. The mixture was allowed to cool to room temperature, diluted withEtOAc (50 mL) and washed with water (3×25 mL). The organic layer wasdried over anhydrous MgSO₄, filtered, and the solvent was removed underreduced pressure. The residue was purified by flash chromatography (20%EtOAc in Hex) to yield 102 mg of Compound 152 as a colourless oil.

Example 53 Preparation of Compound 153

A mixture of 4-hydroxy-3-(trifluoromethyl)benzaldehyde (250 mg, 1.31mmol), benzyl bromide (230 μL, 1.94 mmol) and K₂CO₃ (272 mg, 1.97 mmol)in acetone (5 mL) was stirred at reflux for 16 h, and then was allowedto cool to room temperature, filtered and washed with acetone. Thefiltrate was concentrated under reduced pressure, and the residue waspurified by flash chromatography (20% EtOAc in Hex) to yield 161 mg of4-(benzyloxy)-3-(trifluoromethyl)benzaldehyde as a white solid.

A mixture of 4-(benzyloxy)-3-(trifluoromethyl)benzaldehyde (161 mg,0.574 mmol), 2-butanone (50 μL, 0.555 mmol) and 85% KOH (114 mg, 1.73mmol) in MeOH (2 mL) and water (0.4 mL) was stirred in a sealed tube at75° C. for 1 h. The reaction was allowed to cool to room temperature,diluted with EtOAc (35 mL) and washed with water (2×25 mL). The organiclayer was dried over anhydrous MgSO₄, filtered, and the solvent wasremoved under reduced pressure. The residue was purified by flashchromatography (10% EtOAc in Hex) to yield 38 mg of1-[4-(benzyloxy)-3-(trifluoromethyl)phenyl]pent-1-en-3-one as a whitesolid.

1-[4-(benzyloxy)-3-(trifluoromethyl)phenyl]pent-1-en-3-one (38 mg, 0.114mmol) and 10% Pd on C (4 mg) were combined in EtOAc (3 mL) under argon.AcOH (3 drops) was added. The flask was evacuated and back-filled withhydrogen (balloon). The reaction mixture was stirred for 32 h, and thenwas filtered and washed with EtOAc. The filtrate was concentrated underreduced pressure to yield 22 mg of1-[4-(benzyloxy)-3-(trifluoromethyl)phenyl]pentan-3-one as a colourlessoil.

A mixture of 1-[4-(benzyloxy)-3-(trifluoromethyl)phenyl]pentan-3-one (22mg, 0.089 mmol), K₂CO₃ (20 mg, 0.145 mmol), and 2-chlorobenzothiazole(20 μL, 0.154 mmol) in DMF (1 mL) was stirred in a sealed tube at 100°C. for 16 h. The mixture was allowed to cool to room temperature,diluted with EtOAc (50 mL) and washed with water (3×25 mL). The organiclayer was dried over anhydrous MgSO₄, filtered, and the solvent wasremoved under reduced pressure. The residue was purified by flashchromatography (20% EtOAc in Hex) to yield 22 mg of Compound 153 as acolourless oil.

Example 54 Preparation of Compound 154

To a stirred mixture of Compound 152 (94 mg, 0.285 mmol) and K₂CO₃ (4mg, 0.029 mmol) in DMF (2 mL) under argon was added CF₃TMS (60 μL, 0.406mmol). The reaction mixture was stirred at room temperature for 18 h,and then was diluted with EtOAc (35 mL) and washed with water (2×25 mL).The organic layer was dried over anhydrous MgSO₄, filtered, and thesolvent was removed under reduced pressure. The residue was taken up inMeOH (3 mL) and stirred with conc. HCl (0.1 mL) for 1 h. The mixture wasconcentrated under reduced pressure, and the residue was purified byflash chromatography (20% EtOAc in Hex) to yield 86 mg of Compound 154as a colourless gum.

Example 55 Preparation of Compound 155

To a stirred mixture of Compound 153 (22 mg, 0.058 mmol) and K₂CO₃ (1mg, 0.007 mmol) in DMF (1 mL) under argon was added CF₃TMS (12 μL, 0.081mmol). The reaction mixture was stirred at room temperature for 18 h,and then was diluted with EtOAc (35 mL) and washed with water (2×25 mL).The organic layer was dried over anhydrous MgSO₄, filtered, and thesolvent was removed under reduced pressure. The residue was taken up inMeOH (3 mL) and stirred with conc. HCl (0.1 mL) for 1 h. The mixture wasconcentrated under reduced pressure, and the residue was purified byflash chromatography (20% EtOAc in Hex) to yield 18 mg of Compound 155as a colourless oil.

Example 56 Preparation of Compound 156

To a stirred solution of4-[4-(1,3-benzothiazol-2-yloxy)phenyl]butan-2-one prepared as in Example40 (150 mg, 0.504 mmol) in THF (3 mL) at room temperature under argonwas added Ti(O^(i)Pr)₄ (200 μL, 0.676 mmol), followed by pyrrolidine(100 μL, 1.22 mmol). The reaction mixture was stirred at reflux for 18h, and then was allowed to cool to room temperature. NaBH₄ (28 mg, 0.740mmol) was added, the reaction mixture was stirred for 1 h, and then wasquenched with water (25 mL) and extracted with EtOAc (35 mL). Theorganic layer was dried over anhydrous MgSO₄, filtered, and the solventwas removed under reduced pressure. The residue was purified by flashchromatography (EtOAc/MeOH/Et₃N, 9:1:0.1) to yield 60 mg of Compound 156as a yellow oil.

Example 57 Preparation of Compound 157

To a stirred solution of4-[4-(1,3-benzothiazol-2-yloxy)phenyl]butan-2-one prepared as in Example40 (150 mg, 0.504 mmol) in DCE (3 mL) at room temperature under argonwas added 4A molecular sieves powder (150 mg), L-proline (75 mg, 0.651mmol), AcOH (100 μL, 1.75 mmol), followed by NaBH(OAc)₃ (214 mg, 1.01mmol). The reaction mixture was stirred for 18 h and then was quenchedwith water (25 mL) and extracted with EtOAc (35 mL) and CH₂Cl₂ (2×35mL). The combined organic layer was dried over anhydrous MgSO₄,filtered, and the solvent was removed under reduced pressure. Theresidue was purified by flash chromatography (10% MeOH in CH₂Cl₂+1%AcOH) to yield 80 mg of Compound 157 as a wax.

Example 58 Preparation of Compound 158

To a stirred solution of Compound 148 prepared as in Example 48 (150 mg,0.482 mmol) in DCE (3 mL) at room temperature under argon was added 4Amolecular sieves powder (150 mg), pyrrolidine (50 μL, 0.609 mmol), AcOH(55 μL, 0.961 mmol), followed by NaBH(OAc)₃ (204 mg, 0.962 mmol). Thereaction mixture was stirred for 18 h, and then was quenched with water(25 mL) and extracted with CH₂Cl₂ (3×35 mL). The combined organic layerwas dried over anhydrous MgSO₄, filtered, and the solvent was removedunder reduced pressure. The residue was purified by flash chromatography(EtOAc/MeOH/Et₃N, 9:1:0.1) to yield 160 mg of Compound 158 as colourlesswax.

Example 59 Preparation of Compound 159

A mixture of 4-hydroxyacetophenone (109, 500 mg, 3.67 mmol), K₂CO₃ (435mg, 3.15 mmol), and 2-chlorobenzothiazole (525 μL, 4.04 mmol) in DMF (5mL) was stirred at 140° C. for 18 h. The mixture was allowed to cool toroom temperature, diluted with H₂O (10 mL) and EtOAc (30 mL), separated,and the organic layer was washed with 5% NaOH (2×20 mL), then brine(3×30 mL), dried over anhydrous MgSO₄, filtered, and the solvent wasremoved under reduced pressure. The residue was purified by flashchromatography (30% EtOAc in Hex) to yield 979 mg of Compound 159 as ayellow solid.

Example 60 Preparation of Compound 160

To a stirred solution of Compound 159 (100 mg, 0.371 mmol, prepared asin Example 59) in MeOH (2 mL) at room temperature under argon was addedNaBH₄ (21 mg, 0.555 mmol). The reaction mixture was stirred for 2 h andthen was quenched with water (25 mL) and extracted with CH₂Cl₂ (3×25mL). The combined organic layer was dried over anhydrous MgSO₄,filtered, and the solvent was removed under reduced pressure. Theresidue was purified by flash chromatography (30% EtOAc in Hex) to yield40 mg of Compound 160 as a white solid.

Example 61 Preparation of Compound 161

Following the general procedure for Grignard Additions as disclosedherein, Compound 161 was prepared from Compound 159 (233 mg, 0.865 mmol,prepared as in Example 59), THF (4.0 mL), and ethyl magnesium bromide(0.57 mL, 3 M in Et₂O). Flash column chromatography of the crude mixtureon silica gel (30% EtOAc in Hex) yielded 169 mg of Compound 161 as ayellow oil.

Example 62 Preparation of Compound 162

To a stirred solution of Compound 159 (200 mg, 0.743 mmol, prepared asin Example 91) in THF (8 mL) at room temperature under argon was addedTi(OiPr)₄ (265 μL, 0.895 mmol), followed by pyrrolidine (85 μL, 1.04mmol). The reaction mixture was stirred at reflux for 16 h, and then wasallowed to cool to room temperature. NaBH₄ (42 mg, 1.11 mmol) was added,the reaction mixture was stirred for 1.5 h, and then was quenched withwater (25 mL) and extracted with EtOAc (2×35 mL). The organic layer waswashed with water (35 mL), dried over anhydrous MgSO₄, filtered, and thesolvent was removed under reduced pressure. The residue was purified byflash chromatography (EtOAc/MeOH/Et₃N, 9:1:0.1) to yield 88 mg ofCompound 162 as a yellow oil.

Example 63 Preparation of Compound 163

To a stirred mixture of Compound 159 (125 mg, 0.464 mmol, prepared as inExample 59) and K₂CO₃ (6 mg, 0.043 mmol) in DMF (2 mL) under argon wasadded CF₃TMS (90 μL, 0.610 mmol). The reaction mixture was stirred atroom temperature for 18 h, and then was diluted with EtOAc (35 mL) andwashed with water (2×25 mL). The organic layer was dried over anhydrousMgSO₄, filtered, and the solvent was removed under reduced pressure. Theresidue was taken-up in MeOH (2 mL) and stirred with conc. HCl (0.1 mL)for 1 h. The solvent was removed under reduced pressure, and the residuewas purified by flash chromatography (10% EtOAc in Hex) to yield 26 mgof Compound 163 as an off-white solid.

Example 64 Preparation of Compound 164

A mixture of 4-hydroxybenzaldehyde (84, 200 mg, 1.64 mmol), K₂CO₃ (340mg, 2.46 mmol), and 2-chlorobenzothiazole (260 μL, 2.00 mmol) in DMF (3mL) was stirred in a sealed tube at 100° C. for 16 h. The mixture wasallowed to cool to room temperature, diluted with EtOAc (35 mL), washedwith water (3×25 mL), dried over anhydrous MgSO₄, filtered, and thesolvent was removed under reduced pressure. The residue was purified byflash chromatography (20% EtOAc in Hex) to yield 354 mg of4-(1,3-benzothiazol-2-yloxy)benzaldehyde as a white solid.

To a stirred mixture of 4-(1,3-benzothiazol-2-yloxy)benzaldehyde (150mg, 0.588 mmol) in DCE (3 mL) at room temperature under argon was addedpyrrolidine (60 μL, 0.730 mmol), followed by NaBH(OAc)₃ (190 mg, 0.896mmol). The reaction mixture was stirred for 18 h, and then was quenchedwith water (25 mL) and extracted with CH₂Cl₂ (3×35 mL). The combinedorganic layer was dried over anhydrous MgSO₄, filtered, and the solventwas removed under reduced pressure. The residue was purified by flashchromatography (EtOAc/MeOH/Et₃N, 9:1:0.1) to yield 153 mg of Compound164 as a colourless oil.

Example 65 Preparation of Compound 165

Following the procedure previously described for making Compound 157,and making non-critical variations to use L-proline (81 mg, 0.704 mmol),4-(1,3-benzothiazol-2-yloxy)benzaldehyde (150 mg, 0.588 mmol) in DCE (3mL) at room temperature under argon and NaBH(OAc)₃ (190 mg, 0.896 mmol)and purification using 10% MeOH in CH₂Cl₂+1.5% AcOH as eluent yielded132 mg of Compound 165 as a white solid.

Example 66 Preparation of Compound 166

To a stirred mixture of 4-(1,3-benzothiazol-2-yloxy)benzaldehyde (125mg, 0.490 mmol) and K₂CO₃ (7 mg, 0.051 mmol) in DMF (2 mL) under argonwas added CF₃TMS (94 μL, 0.655 mmol). The reaction mixture was stirredat room temperature for 18 h, and then was diluted with EtOAc (35 mL)and washed with water (2×25 mL). The organic layer was dried overanhydrous MgSO₄, filtered, and the solvent was removed under reducedpressure. The residue was taken-up in MeOH (2 mL) and stirred with conc.HCl (0.1 mL) for 1 h. The solvent was removed under reduced pressure,and the residue was purified by flash chromatography (20% EtOAc in Hex)to yield 94 mg of Compound 166 as white solid.

Example 67 Preparation of Compound 167

A mixture of 3-chloro-4-hydroxybenzothiazole (250 mg, 1.60 mmol), K₂CO₃(332 mg, 2.40 mmol), and 2-chlorobenzothiazole (260 μL, 2.00 mmol) inDMF (3 mL) was stirred in a sealed tube at 100° C. for 18 h. The mixturewas allowed to cool to room temperature, diluted with EtOAc (35 mL),washed with water (3×25 mL), dried over anhydrous MgSO₄, filtered, andthe solvent was removed under reduced pressure. The residue was purifiedby flash chromatography (20% EtOAc in Hex) to yield 187 mg of4-(1,3-benzothiazol-2-yloxy)-3-chlorobenzaldehyde as a white solid.

To a stirred mixture of4-(1,3-benzothiazol-2-yloxy)-3-chlorobenzaldehyde (187 mg, 0.645 mmol)and K₂CO₃ (9 mg, 0.065 mmol) in DMF (2 mL) under argon was added CF₃TMS(143 μL, 0.968 mmol). The reaction mixture was stirred at roomtemperature for 4 days, and then was diluted with EtOAc (40 mL) andwashed with water (2×25 mL). The organic layer was dried over anhydrousMgSO₄, filtered, and the solvent was removed under reduced pressure. Theresidue was taken-up in MeOH (3 mL) and stirred with conc. HCl (0.2 mL)for 1 h. The mixture was diluted with EtOAc (40 mL) and washed withwater (2×25 mL). The organic layer was dried over anhydrous MgSO₄,filtered, and the solvent was removed under reduced pressure. Theresidue was purified by flash chromatography (20% EtOAc in Hex) to yield90 mg of Compound 167 as a white solid.

Example 68 Preparation of Compound 168

A mixture of 4-(1,3-benzothiazol-2-yloxy)benzaldehyde (300 mg, 1.18mmol, prepared as in Example 64), 4A molecular sieves (600 mg) andethylamine (2.0 M solution in THF, 3.0 mL, 6.0 mmol) was stirred underargon at room temperature for 3 h. The reaction mixture was filtered,and the solvent was removed under reduced pressure to yield crude1-[4-(1,3-benzothiazol-2-yloxy)phenyl]-N-ethylmethanimine.

To 1-[4-(1,3-benzothiazol-2-yloxy)phenyl]-N-ethylmethanimine (1.18 mmol)and KHF₂ (69 mg, 0.883 mmol) in MeCN (4 mL) and DMF (274 μL) at 0° C.under argon was added TFA (113 μl, 1.48 mmol). The mixture was stirredfor 5 minutes, and then CF₃TMS (261 μL, 1.78 mmol) was added. Thecooling bath was removed, and the reaction mixture was stirred for 18 h.It was diluted with saturated aqueous Na₂CO₃ (40 mL) and extracted withEtOAc (40 mL). The organic layer was washed with water (25 mL), driedover anhydrous MgSO₄, filtered, and the solvent was removed underreduced pressure. The residue was purified by flash chromatography (5%EtOAc in Hex) to yield 294 mg of a yellow oil.

To further purify the desired compound, to the oil in MeOH (2 mL) wasadded NaBH₄ (30 mg), and the mixture was stirred under argon for 30minutes. The reaction was quenched with water (25 mL) and extracted withEtOAc (35 mL). The organic layer was dried over anhydrous Na₂SO₄,filtered, and the solvent was removed under reduced pressure. Theresidue was purified by flash chromatography (10% EtOAc in Hex) to yield133 mg of Compound 168 as a colourless oil.

Example 69 Preparation of Compound 169

A mixture of 4′-fluoroacetophenone (177, 150 μL, 1.24 mmol),2-methyl-5-benzothiazolol (205 mg, 1.24 mmol) and K₂CO₃ (514 mg, 3.72mmol) in DMSO (3 mL) was stirred in a sealed tube at 100° C. for 18 h,and then was allowed to cool to room temperature, diluted with EtOAc (35mL), washed with 1 M NaOH (2×25 mL) and water (25 mL). The organic layerwas dried over anhydrous Na₂SO₄, filtered, and the solvent was removedunder reduced pressure. The residue was purified by flash chromatography(20% EtOAc in Hex) to yield 306 mg of Compound 169 as an off-whitesolid.

Example 70 Preparation of Compound 170

To a stirred mixture of Compound 169 (150 mg, 0.529 mmol, prepared as inExample 69) and K₂CO₃ (7 mg, 0.051 mmol) in DMF (3 mL) under argon wasadded CF₃TMS (195 μL, 1.32 mmol). The reaction mixture was stirred atroom temperature for 5 days, and then was diluted with EtOAc (35 mL) andwashed with water (2×25 mL). The organic layer was dried over anhydrousNa₂SO₄, filtered, and the solvent was removed under reduced pressure.The residue was taken-up in MeOH (3 mL) and stirred with conc. HCl (0.3mL) for 1 h. The mixture was diluted with EtOAc (35 mL) and washed withsaturated aqueous solution of Na₂CO₃ (2×25 mL). The organic layer wasdried over anhydrous Na₂SO₄, filtered, and the solvent was removed underreduced pressure.

To further purify the desired compound, to the residue in MeOH (3 mL)was added 20 mg of NaBH₄. The reaction was stirred for 1 h, and then wasquenched with water (25 mL) and extracted with EtOAc (35 mL). Theorganic layer was washed with water (25 mL), dried over anhydrousNa₂SO₄, filtered, and the solvent was removed under reduced pressure.The residue was purified by flash chromatography (30% EtOAc in Hex) toyield 52 mg of Compound 170 as an off-white solid.

Example 71 Preparation of Compound 171

To a suspension of Compound 169 prepared as in Example 69 (75 mg, 0.265mmol) in MeOH (2 mL) was added NaBH₄ (15 mg, 0.396 mmol). The mixturewas stirred under argon for 1 h, after which time 10 mg of NaBH₄ wasadded. The mixture was stirred for 30 minutes, after which time a clearsolution was observed. The reaction was quenched with water (25 mL) andextracted with EtOAc (35 mL). The organic layer was washed with water(25 mL), dried over anhydrous Na₂SO₄, filtered, and the solvent wasremoved under reduced pressure to yield 40 mg of Compound 171 as ayellowish oil.

Example 72 Preparation of Compound 172

To a solution of acetovanillone (250 mg, 1.50 mmol) in DMF (5 mL) underargon was added 2-chlorobenzothiazole (235 μL, 1.80 mmol) and K₂CO₃ (311mg, 2.25 mmol). The reaction mixture was stirred in a sealed tube at100° C. for 18 hours. The reaction mixture was diluted with ethylacetate (35 mL). The organic layer was then washed with 1M aqueous NaOH(2×25 mL) and water (25 mL). The organic layer was dried over Na₂SO₄,filtered, and the solvent was removed under reduced pressure. Flashcolumn chromatography on silica gel (20% EtOAc in Hex yielded 437 mg ofCompound 172 as a white solid.

Example 73 Preparation of Compound 173

To a stirred mixture of Compound 172 (150 mg, 0.501 mmol) and K₂CO₃ (7mg, 0.051 mmol) in DMF (3 mL) under argon was added CF₃TMS (111 μL,0.752 mmol). The reaction mixture was stirred at room temperature for 44hours then additional CF₃TMS (222 μL, 1.54 mmol) was added and stirringcontinued for 3 days. The mixture was then diluted with EtOAc (35 mL)and washed with water (25 mL). The organic layer was dried overanhydrous Na₂SO₄, filtered, and the solvent was removed under reducedpressure. The residue was taken-up in MeOH (3 mL) and stirred with conc.HCl (0.3 mL) for 1 hour. The mixture was diluted with EtOAc (35 mL) andwashed with water (25 mL). The organic layer was dried over anhydrousNa₂SO₄, filtered, and the solvent was removed under reduced pressure.

In order to separate the product from by-products the residue wastaken-up in MeOH (3 mL), NaBH₄ (22 mg) was added and the mixture wasstirred for 30 minutes. The mixture was diluted with EtOAc (35 mL) andwashed with water (25 mL). The organic layer was dried over anhydrousNa₂SO₄, filtered, and the solvent was removed under reduced pressure.The residue was purified by flash chromatography (20% EtOAc in Hex) toyield 56 mg of Compound 173 as a white solid.

Example 74 Preparation of Compound 174

To a stirred solution of 3-chloro-4-hydroxybenzaldehyde (900 mg, 5.75mmol) in Acetone (10 mL)/H₂O (10 mL) was added NaOH (1 g, 25 mmol). Themixture was stirred at room temperature for 18 h. The reaction wasquenched with the addition of 5% aq. HCl (10 mL) and extracted withEtOAc (15 mL). The organic layer was washed with water (2×10 mL), brine(10 mL), dried over anhydrous MgSO₄, filtered, and the solvent wasremoved under reduced pressure to yield 1.1 g of4-(3-chloro-4-hydroxyphenyl)but-3-en-2-one as a yellow oil.

To a stirred solution of 4-(3-chloro-4-hydroxyphenyl)but-3-en-2-one (626mg, 3.18 mmol) in EtOAc (12 mL) was added 10% Pd/C (100 mg). Thereaction mixture was stirred under hydrogen for 1.5 h after. The mixturewas filtered, the solvent was removed under reduced pressure, and theresidue was purified by flash chromatography (25% EtOAc in Hex) to yield333 mg of 4-(3-chloro-4-hydroxyphenyl)butan-2-one as an oil.

To a solution of 4-(3-chloro-4-hydroxyphenyl)butan-2-one (333 mg, 1.67mmol) in DMF (5 mL) under argon was added 2-chlorobenzothiazole (239 μL,1.84 mmol) and K₂CO₃ (231 mg, 1.67 mmol). The reaction mixture wasstirred at 140° C. for 18 hours. The reaction mixture was allowed tocool to room temperature, and then was diluted with water (30 mL) andextracted with EtOAc (40 mL). The organic layer was washed with brine(3×40 mL). The organic layer was dried (MgSO₄), filtered, and thesolvent was removed under reduced pressure. Flash column chromatographyon silica gel (25% EtOAc in Hex) yielded 429 mg of Compound 174 as ayellow oil.

Example 75 Preparation of Compound 175

Following General Procedure for CF₃TMS Additions as disclosed herein,Compound 175 was prepared from Compound 174 (105 mg, 0.36 mmol), CF₃TMS(97 μL, 0.65 mmol), K₂CO₃ (15 mg, 0.11 mmol) and DMF (2 mL) then MeOH (5mL) and HCl (250 μL). Flash column chromatography of the crude mixtureon silica gel (20% EtOAc in Hex) yielded 109 mg of Compound 175 as anoil.

Example 76 Preparation of Compound 176

A mixture of 4-hydroxyacetophenone (150 mg, 1.10 mmol), K₂CO₃ (228 mg,1.65 mmol), and 2-chloro-4-(methylthio)-benzothiazole (297 mg, 1.38mmol) in DMF (3 mL) was stirred at 100° C. for 18 h in a sealed tube.The mixture was allowed to cool to room temperature, diluted with H₂O(10 mL) and EtOAc (30 mL), separated, and the organic layer was washedwith 5% NaOH (2×20 mL), then brine (3×30 mL), dried over anhydrousMgSO₄, filtered, and the solvent was removed under reduced pressure. Theresidue was purified by flash chromatography (20% EtOAc in Hex) to yield338 mg of1-(4-{[4-(methylsulfanyl)-1,3-benzothiazol-2-yl]oxy}phenyl)ethan-1-oneas a white solid.

To a stirred solution of1-(4-{[4-(methylsulfanyl)-1,3-benzothiazol-2-yl]oxy}phenyl)ethan-1-one(150 mg, 0.476 mmol) in MeOH (10 mL) at room temperature under argon wasadded NaBH₄ (27 mg, 0.714 mmol). The reaction mixture was stirred for 1h and then was quenched with water (25 mL) and extracted with EtAOc (35mL). The organic layer was dried over anhydrous MgSO₄, filtered, and thesolvent was removed under reduced pressure. The residue was purified byflash chromatography (20% EtOAc in Hex) to yield 134 mg of Compound 176as a colorless oil.

Example 77 Preparation of Compound 177

To a stirred solution of Compound 159 (150 mg, 0.557 mmol) in diethylether (9 mL) at 0° C. under argon was added 3.0M MeMgBr in ether (0.3mL, 0.9 mmol). The reaction mixture was stirred for 10 minutes at 0° C.The cooling bath was removed and the reaction was stirred for 1 hourthen quenched with water (10 mL), diluted with 5% HCl (10 mL) andextracted with EtAOc (35 mL). The organic layer was washed with water(20 mL), dried over anhydrous MgSO₄, filtered, and the solvent wasremoved under reduced pressure. The residue was purified by flashchromatography (20% EtOAc in Hex) to yield 93 mg of Compound 177 as acolorless oil.

Example 78 Preparation of Compound 178

A mixture of 4-(1,3-benzothiazol-2-yloxy)benzaldehyde (300 mg, 1.18mmol, prepared as in Example 64), 4A molecular sieves (600 mg),methylamine (2.0 M solution in THF, 3.0 mL, 6.0 mmol) and anhydrous DCE(3.0 mL) was stirred under argon at room temperature for 18 h. Thereaction mixture was filtered and the solvent was removed under reducedpressure to yield crude1-[4-(1,3-benzothiazol-2-yloxy)phenyl]-N-methylmethanimine.

To 1-[4-(1,3-benzothiazol-2-yloxy)phenyl]-N-methylmethanimine (1.18mmol) and KHF₂ (69 mg, 0.883 mmol) in MeCN (4 mL) and DMF (274 μL) at 0°C. under argon was added TFA (113 μl, 1.48 mmol). The mixture wasstirred for 5 minutes, and then CF₃TMS (261 μL, 1.78 mmol) was added.The cooling bath was removed, and the reaction mixture was stirred for20 h. It was diluted with saturated aqueous Na₂CO₃ (40 mL) and extractedwith EtOAc (40 mL). The organic layer was washed with water (25 mL),dried over anhydrous Na₂SO₄, filtered, and the solvent was removed underreduced pressure.

The residue was taken-up in MeOH (2 mL), NaBH₄ (45 mg) was added, andthe mixture was stirred under argon for 30 minutes. The reaction wasquenched with water (25 mL) and extracted with EtOAc (35 mL). Theorganic layer was dried over anhydrous Na₂SO₄, filtered, and the solventwas removed under reduced pressure. The residue was purified by flashchromatography (20% EtOAc in Hex) to yield 109 mg of Compound 178 as acolourless oil.

Example 79 Preparation of Compound 179

A mixture of 4-hydroxybenzaldehyde (100 mg, 0.819 mmol), K₂CO₃ (170 mg,1.23 mmol), and 2-chloro-4,6-difluoro-benzothiazole (168 mg, 0.817 mmol)in DMF (3 mL) was stirred in a sealed tube at 100° C. for 18 h. Themixture was allowed to cool to room temperature, diluted with EtOAc (35mL), washed with 1M NaOH (2×25 mL) and water (25 mL), dried overanhydrous Na₂SO₄, filtered, and the solvent was removed under reducedpressure to yield 216 mg of4-(4,6-difluoro-1,3-benzothiazol-2-yloxy)benzaldehyde as a white solid.

To a stirred mixture of4-(4,6-difluoro-1,3-benzothiazol-2-yloxy)benzaldehyde (216 mg, 0.742mmol) and K₂CO₃ (10 mg, 0.072 mmol) in DMF (2 mL) under argon was addedCF₃TMS (220 μl, 1.49 mmol). The reaction mixture was stirred at roomtemperature for 20 h, and then was diluted with EtOAc (35 mL) and washedwith water (25 mL). The organic layer was dried over anhydrous Na₂SO₄,filtered, and the solvent was removed under reduced pressure. Theresidue was taken-up in MeOH (3 mL) and stirred with conc. HCl (0.3 mL)for 1 h. EtOAc (35 mL) was added and the mixture was washed with water(25 mL). The organic layer was dried over anhydrous Na₂SO₄, andfiltered. The solvent was removed under reduced pressure and the residuewas purified by flash chromatography (20% EtOAc in Hex) to yield 116 mgof Compound 179 as a white solid.

Example 80 Preparation of Compound 180

A mixture of 4-hydroxyacetophenone (150 mg, 1.10 mmol), K₂CO₃ (228 mg,1.65 mmol), and 2-chloro-4,6-difluoro-benzothiazole (226 mg, 1.10 mmol)in DMF (3 mL) was stirred at 100° C. for 18 h in a sealed tube. Themixture was allowed to cool to room temperature, diluted with EtOAc (35mL), separated, and the organic layer was washed with 1M NaOH (2×25 mL),then water (25 mL), dried over anhydrous Na₂SO₄, filtered, and thesolvent was removed under reduced pressure to yield 335 mg of1-[4-(4,6-difluoro-1,3-benzothiazol-2-yloxy)phenyl]ethan-1-one as alight brown solid.

To a stirred solution of1-[4-(4,6-difluoro-1,3-benzothiazol-2-yloxy)phenyl]ethan-1-one (100 mg,0.328 mmol) in MeOH (2 mL) at room temperature under argon was addedNaBH₄ (18 mg, 0.476 mmol). The reaction mixture was stirred for 1 h andthen was quenched with water (25 mL) and extracted with EtOAc (35 mL).The organic layer was dried over anhydrous Na₂SO₄, filtered, and thesolvent was removed under reduced pressure. The residue was purified byflash chromatography (30% EtOAc in Hex) to yield 80 mg of Compound 180as a colourless oil.

Example 81 Preparation of Compound 181

To a stirred solution of1-[4-(4,6-difluoro-1,3-benzothiazol-2-yloxy)phenyl]ethan-1-one (150 mg,0.491 mmol) and K₂CO₃ (7 mg, 0.051 mmol) in DMF (3 mL) under argon wasadded CF₃TMS (145 μL, 0.982 mmol). The reaction mixture was stirred atroom temperature for 4 days then diluted with EtOAc (35 mL) and washedwith water (25 mL). The organic layer was dried over anhydrous Na₂SO₄,filtered, and the solvent was removed under reduced pressure. Theresidue was taken-up in MeOH (3 mL) and stirred with conc. HCl (0.3 mL)for 1 h. EtOAc (35 mL) was added and the mixture was washed with water(25 mL). The residue was taken-up in MeOH (3 mL), NaBH₄ (27 mg) wasadded and the mixture was stirred for 1 h. EtOAc (35 mL) was added andthe mixture was washed with water (25 mL). The organic layer was driedover anhydrous Na₂SO₄, and filtered. The solvent was removed underreduced pressure and the residue was purified by flash chromatography(20% EtOAc in Hex) to yield 27 mg of Compound 181 as a white solid.

Example 82 Preparation of Compound 182

A mixture of 4-hydroxy-2-methoxybenzaldehyde (250 mg, 1.64 mmol), K₂CO₃(340 mg, 2.46 mmol), and 2-chlorobenzothiazole (215 μL, 1.65 mmol) inDMF (5 mL) was stirred in a sealed tube at 100° C. for 18 h. The mixturewas allowed to cool to room temperature, diluted with EtOAc (35 mL),washed with 1M NaOH (2×25 mL) and water (25 mL), dried over anhydrousNa₂SO₄, filtered, and the solvent was removed under reduced pressure andthe residue was purified by flash chromatography (20% EtOAc in Hex) toyield 457 mg of 4-(1,3-benzothiazol-2-yloxy)-2-methoxybenzaldehyde as awhite solid.

To a stirred mixture of4-(1,3-benzothiazol-2-yloxy)-2-methoxybenzaldehyde (200 mg, 0.701 mmol)and K₂CO₃ (10 mg, 0.072 mmol) in DMF (3 mL) under argon was added CF₃TMS(207 μl, 1.402 mmol). The reaction mixture was stirred at roomtemperature for 20 h then was diluted with EtOAc (35 mL) and washed withwater (25 mL). The organic layer was dried over anhydrous Na₂SO₄,filtered, and the solvent was removed under reduced pressure. Theresidue was taken-up in MeOH (3 mL) and stirred with conc. HCl (0.3 mL)for 1 h. EtOAc (35 mL) was added and the mixture was washed with water(25 mL). The organic layer was dried over anhydrous Na₂SO₄, andfiltered. The solvent was removed under reduced pressure and the residuewas purified by flash chromatography (20% EtOAc in Hex) to yield 172 mgof Compound 182 as a white solid.

Example 83 Preparation of Compound 183

To a stirred mixture of 4-(4-hydroxyphenyl)-2-butanone (150 mg, 0.914mmol) and K₂CO₃ (13 mg, 0.094 mmol) in DMF (2 mL) at 0° C. under argonwas added CF₃TMS (340 μL, 2.30 mmol) dropwise. The reaction mixture wasstirred at room temperature for 42 hours. The mixture was diluted withEtOAc (20 mL), washed with water (2×20 mL), dried over anhydrous Na₂SO₄,filtered, and the solvent was removed under reduced pressure. To theresidue were added MeOH (3 mL) and 6N aqueous HCl (0.3 mL), and thereaction was stirred for 1 hour. The reaction was diluted with EtOAc (20mL), washed with saturated aqueous NaHCO₃ solution (2×20 mL), water (20mL), dried over anhydrous Na₂SO₄, filtered, and the solvent was removedunder reduced pressure. The residue was purified by flash chromatography(20% EtOAc in hexane) to yield 145 mg of4-(4,4,4-trifluoro-3-hydroxy-3-methylbutyl)phenol as a white solid.

In analogy to the procedure of Example 97, 173 mg of Compound 183 wasprepared as a white solid from4-(4,4,4-trifluoro-3-hydroxy-3-methylbutyl)phenol (145 mg, 0.619 mmol),2-(chloromethyl)quinoline hydrochloride (146 mg, 0.682 mmol), and K₂CO₃(342 mg, 2.47 mmol) in DMF (2 mL).

Example 84 Preparation of Compound 184

A mixture of vanillylacetone (250 mg, 1.52 mmol), K₂CO₃ (377 mg, 2.73mmol), and 2-(chloromethyl)quinoline hydrochloride (343 mg, 1.60 mmol)in DMF (6 mL) was stirred in a sealed tube at 130° C. for 22 h. Themixture was allowed to cool to room temperature. Water (20 mL) was addedand the mixture was extracted with EtOAc (3×20 mL). The combined organiclayers were dried over Na₂SO₄, filtered, and the solvent was removedunder reduced pressure. The residue was purified by flash chromatography(25% EtOAc in Hex) to yield 344 mg of4-{3-methoxy-4-[(quinoline-2-yl)methoxy]phenyl}butan-2-one as a yellowoil.

To a stirred mixture of4-{3-methoxy-4-[(quinoline-2-yl)methoxy]phenyl}butan-2-one (120 mg, 0.36mmol) and K₂CO₃ (33 mg, 0.24 mmol) in DMF (3 mL) under argon was addedCF₃TMS (175 μL, 1.18 mmol). The reaction mixture was stirred at roomtemperature for 21 h then was diluted with EtOAc (25 mL) and washed withbrine (25 mL). The organic layer was dried over anhydrous Na₂SO₄,filtered, and the solvent was removed under reduced pressure. Theresidue was taken-up in MeOH (5 mL) and stirred with conc. HCl (0.2 mL)for 75 minutes. The solvent was removed under reduced pressure, EtOAc(25 mL) was added and the mixtures was washed with water (25 mL), driedover Na₂SO₄, filtered, and concentrated, The residue was purified byflash chromatography (25% EtOAc in Hex) to yield 100 mg of Compound 184as an off-white solid.

Example 85 Preparation of Compound 185

A mixture of 1-(4-hydroxyphenyl)pentan-3-one (175 mg, 0.98 mmol,prepared as in Example 48), K₂CO₃ (150 mg, 1.09 mmol), and2-(chloromethyl)quinoline hydrochloride (150 mg, 0.70 mmol) in DMF (3mL) was stirred in a sealed tube at 140° C. for 20 h. The mixture wasallowed to cool to room temperature, water (25 mL) was added and themixture was extracted with EtOAc (3×25 mL). The combined organic layerswere washed with brine (25 mL), dried over Na₂SO₄, filtered, and thesolvent was removed under reduced pressure. The residue was purified byflash chromatography (25% EtOAc in Hex) to yield 254 mg of1-{4-[(quinoline-2-yl)methoxy]phenyl}pentan-3-one as a yellow oil.

To a stirred mixture of1-{4-[(quinoline-2-yl)methoxy]phenyl}pentan-3-one (135 mg, 0.42 mmol)and K₂CO₃ (40 mg, 0.29 mmol) in DMF (3 mL) under argon was added CF₃TMS(200 μl, 1.35 mmol). The reaction mixture was stirred at roomtemperature for 20 h then was diluted with EtOAc (35 mL), washed withwater (2×50 mL) and brine (15 mL). The organic layer was dried overanhydrous Na₂SO₄, filtered, and the solvent was removed under reducedpressure. The residue was taken-up in MeOH (5 mL) and stirred with conc.HCl (0.2 mL) for 1 h. The solvent was removed under reduced pressure,EtOAc (25 mL) was added and the mixture was washed with water (25 mL),dried over Na₂SO₄, filtered, and concentrated. The residue was purifiedby flash chromatography (25% EtOAc in Hex) to yield 83 mg of Compound185.

Example 86 Preparation of Compound 186

Following general procedure for reductions, Compound 186 was preparedfrom Compound 113 (105 mg, 0.265 mmol, prepared as in Example 13),sodium borohydride (20 mg, 0.529 mmol), and methanol (2 mL). Flashcolumn chromatography of the crude mixture on silica gel (20% EtOAc inHex) yielded 0.083 g of Compound 186 as a colourless glass.

Example 87 Preparation of Compound 187

Following general procedure for reductions, Compound 187 was preparedfrom Compound 114 (115 mg, 0.301 mmol, prepared as in Example 14),sodium borohydride (23 mg, 0.608 mmol), and methanol (2 mL). Flashcolumn chromatography of the crude mixture on silica gel (20% EtOAc inHex) yielded 0.080 g of Compound 187 as a colourless glass.

Example 88 Preparation of Compound 188

To a stirred solution of Compound 101 prepared as in Example 1 (150 mg,0.439 mmol) in DCE (3 mL) at room temperature under argon was added 4Amolecular sieves powder (156 mg), 1-methylpiperazine (70 μL, 0.631mmol), AcOH (100 μL, 1.75 mmol), followed by NaBH(OAc)₃ (190 mg, 0.896mmol). The reaction mixture was stirred for 18 h, and then was quenchedwith saturated NaHCO₃ (25 mL) and extracted with CH₂Cl₂ (2×35 mL). Thecombined organic layer was dried over anhydrous MgSO₄, filtered, and thesolvent was removed under reduced pressure. The residue was purified byflash chromatography (EtOAc/MeOH/Et₃N, 9:1:0.1) to yield 24 mg ofCompound 188 as colourless oil. Compound 188 was then taken-up in CH₂CL₂(2 mL) and stirred with 1.25M HCl in MeOH (0.15 mL) for 1 h. The mixturewas evaporated under reduced pressure to give the hydrochloride salt ofCompound 188 as a colourless foam (27 mg).

Example 89 Preparation of Compound 189

A mixture of 4-(4-hydroxyphenyl)-2-butanone (500 mg, 3.04 mmol), K₂CO₃(443 mg, 3.21 mmol), and 2-(chloromethyl)quinoline hydrochloride (400mg, 1.866 mmol) in DMF (6 mL) was stirred in a sealed tube at 150° C.for 20 h. The mixture was allowed to cool to room temperature. Water (20mL) was added and the mixture was extracted with EtOAc (3×20 mL). Thecombined organic layers were dried over MgSO₄, filtered, and the solventwas removed under reduced pressure. The residue was purified by flashchromatography (20% EtOAc in Hex) to 603 mg of Compound 189 as a yellowoil.

Example 90 Preparation of Compound 190

To a stirred solution of Compound 189 (115 mg, 0.378 mmol, prepared asin Example 89) in DCE (3 mL) at room temperature under argon was addedglacial acetic acid (0.050 mL), NaBH(OAc)₃ and pyrrolidine (40 μL, 1.04mmol). The reaction mixture was stirred at room temperature for 20 h.The reaction was quenched with water (20 mL) and extracted with CH₂CL₂(2×20 mL). The organic layer was washed with brine (20 mL), dried overanhydrous MgSO₄, filtered, and the solvent was removed under reducedpressure. The residue was purified by flash chromatography(EtOAc/MeOH/Et₃N, 9:1:0.1) to yield Compound 190 as a yellow oil.

Example 91 Preparation of Compound 191

To a stirred solution of Compound 118 (154 mg, 0.431 mmol) in anhydrousTHF at 0° C. under argon was added 3.0 M solution of EtMgBr in ether(180 μL, 0.540 mmol) dropwise. The reaction mixture was stirred at 0° C.for 10 minutes, after which time the cooling bath was removed, and thestirring was continued at room temperature for 1 hour. The reaction wasquenched with saturated aqueous NH₄Cl solution (10 mL) and extractedwith EtOAc (15 mL). The organic layer was washed with water (10 mL),dried over anhydrous Na₂SO₄, filtered, and the solvent was removed underreduced pressure. The residue was purified by flash chromatography (30%EtOAc in hexane) to yield 114 mg of Compound 191 as a yellow oil.

The two enantiomers of Compound 191 were separated by HPLC using thefollowing conditions: ChiralPak AD™ column, 5 μm particle size, 4.6×250mm column dimensions; mobile phase: 90% i-PrOH in hexane; flow rate: 1mL/min; injection volume: 50 μL; sample concentration: 1 mg/mL; runtime: 22 minutes; number of injections: 1. Each peak was manuallycollected to create two pools of fractions. 50 μL samples from each poolwere separately injected into the HPLC column, using the same mobilephase and run time as mentioned above. Enantiomer 1 had a retention timeof 17.014 min and >99% purity. Enantiomer 2 had a retention time of18.709 min and >99% purity.

Example 92 Preparation of Compound 192

A mixture of 1-(4-hydroxy-3-methoxyphenyl)pentan-3-one (343 mg, 1.65mmol), K₂CO₃ (342 mg, 2.47 mmol), and2-chloro-4-(methylthio)benzothiazole (392 mg, 1.82 mmol) in DMF (4 mL)was stirred under argon in a sealed tube at 100° C. for 20 h. Themixture was allowed to cool to room temperature, diluted with EtOAc (25mL), washed with water (2×25 mL), dried over anhydrous Na₂SO₄, filtered,and the solvent was removed under reduced pressure. The residue waspurified by flash chromatography (20% EtOAc in Hex) to yield 400 mg ofCompound 192 as a white solid.

Example 93 Preparation of Compound 193

To a stirred suspension of Compound 192 (150 mg, 0.39 mmol) in MeOH (5mL) under argon was added NaBH₄ (22 mg, 0.58 mmol). The reaction mixturewas stirred for 30 minutes, after which time another 22 mg of NaBH₄wasadded. The reaction mixture was stirred for 30 minutes, and then wasdiluted with EtOAc (30 mL), washed with water (2×20 mL), dried overanhydrous Na₂SO₄, filtered, and the solvent was removed under reducedpressure. The residue was triturated with EtOAc/hexane to yield 70 mg ofCompound 193 as a white solid.

Example 94 Preparation of Compound 194

In analogy to the procedure of Example 92, 613 mg of Compound 194 wasprepared as an off-white solid from 1-(4-hydroxyphenyl)pentan-3-one (390mg, 2.19 mmol), 2-chloro-4-(methylthio)benzothiazole (520 mg, 2.41mmol), and K₂CO₃ (454 mg, 3.28 mmol) in DMF (5 mL).

Example 95 Preparation of Compound 195

To a stirred mixture of Compound 194 (150 mg, 0.42 mmol) and K₂CO₃ (6mg, 0.04 mmol) in DMF (3 mL) at 0° C. under argon was added CF₃TMS (160μL, 1.08 mmol) dropwise. The reaction mixture was stirred at roomtemperature for 42 hours. The mixture was diluted with EtOAc (25 mL),washed with water (2×25 mL), dried over anhydrous Na₂SO₄, filtered, andthe solvent was removed under reduced pressure. To the residue wereadded MeOH (2 mL) and 6N aqueous HCl (0.2 mL), and the reaction wasstirred for 1 hour. The reaction was diluted with EtOAc (25 mL), washedwith water (2×25 mL), dried over anhydrous Na₂SO₄, filtered, and thesolvent was removed under reduced pressure. To the residue were addedMeOH (2 mL) and NaBH₄ (10 mg), and the reaction was stirred for 45minutes. The solvent was removed under reduced pressure, and the residuewas purified by flash chromatography (20% EtOAc in hexane) to yield 95mg of Compound 195 as a colorless oil.

Example 96 Preparation of Compound 196

To 1-(4-hydroxy-3-methoxyphenyl)pentan-3-one (1.72 g, 8.26 mmol) in MeOH(20 mL) at 0° C. under argon was added NaBH₄ (469 mg, 12.4 mmol) inportions over 15 minutes. The reaction mixture was stirred at roomtemperature for 1 hour, and then was quenched with water (35 mL) andextracted with EtOAc (50 mL). The organic layer was washed with water(35 mL), dried over anhydrous Na₂SO₄, filtered, and the solvent wasremoved under reduced pressure to yield 1.17 g of4-(3-hydroxypentyl)-2-methoxyphenol as a light yellow oil.

In analogy to the procedure of Example 92, 113 mg of Compound 196 wasprepared as a colorless wax from 4-(3-hydroxypentyl)-2-methoxyphenol(100 mg, 0.48 mmol), 2-chlorobenzothiazole (70 μL, 0.54 mmol), and K₂CO₃(199 mg, 1.44 mmol) in DMF (2 mL).

Example 97 Preparation of Compound 197

To a stirred mixture of 4′-hydroxyacetophenone (150 mg, 1.10 mmol) andK₂CO₃ (15 mg, 0.11 mmol) in DMF (2 mL) at 0° C. under argon was addedCF₃TMS (410 μL, 2.78 mmol) dropwise. The reaction mixture was stirred atroom temperature for 90 hours. The mixture was diluted with EtOAc (20mL), washed with water (2×20 mL), dried over anhydrous Na₂SO₄, filtered,and the solvent was removed under reduced pressure. To the residue wereadded MeOH (3 mL) and 6N aqueous HCl (0.3 mL), and the reaction wasstirred for 1 hour. The reaction was diluted with EtOAc (20 mL), washedwith saturated aqueous NaHCO₃ solution (2×20 mL), water (20 mL), driedover anhydrous Na₂SO₄, filtered, and the solvent was removed underreduced pressure. The residue was purified by flash chromatography (30%EtOAc in hexane) to yield 135 mg of4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenol as a white solid.

A mixture of 4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenol (135 mg,0.655 mmol), K₂CO₃ (362 mg, 2.62 mmol), and 2-(chloromethyl)quinolinehydrochloride (154 mg, 0.719 mmol) in DMF (2 mL) was stirred in a sealedtube at 80° C. for 18 hours. The mixture was allowed to cool to roomtemperature, diluted with EtOAc (20 mL), washed with water (2×20 mL),dried over anhydrous Na₂SO₄, filtered, and the solvent was removed underreduced pressure. The residue was purified by flash chromatography (20%EtOAc in Hex) to yield 156 mg of Compound 197 as a yellowish solid.

Example 98 Preparation of Compound 198

A mixture of 4-[3-hydroxy-3-(trifluoromethyl)pentyl]-2-methoxyphenol(189 mg, 0.679 mmol), K₂CO₃ (375 mg, 2.71 mmol), and2-(chloromethyl)quinoline hydrochloride (160 mg, 0.747 mmol) inanhydrous acetone (4 mL) was stirred in a sealed tube at 60° C. for 18hours. The mixture was allowed to cool to room temperature, filtered,washed with acetone, and the solvent was removed under reduced pressure.The residue was purified by 2 successive flash columns (20% EtOAc inHex, then by 10% EtOAc in CH₂Cl₂) to yield 75 mg of Compound 198 as acolorless glass.

Example 99 Preparation of Compound 199

In analogy to the method for the procedure of4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenol, 132 mg of2-methoxy-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenol was preparedfrom 4′-hydroxy-3′-methoxyacetophenone (150 mg, 0.903 mmol), CF₃TMS (340μl, 2.30 mmol), and K₂CO₃ (12 mg, 0.087 mmol) in DMF (2 mL).

Following the procedure of Example 97, 161 mg of Compound 199 wasprepared as a white solid from2-methoxy-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenol (132 mg, 0.560mmol), 2-(chloromethyl)quinoline hydrochloride (132 mg, 0.620 mmol), andK₂CO₃ (310 mg, 2.24 mmol) in DMF (2 mL).

Example 1000 MC/9 HPLC Assay

Cultured MC/9 cells (3×10″6 cells) in 1 mL HBSS were pre-incubated witha series of concentrations of compound solubilized in DMSO for 30minutes. Production of leukotrienes were stimulated with the addition of1 μM calcium ionophore (A23187), diluted from a 4 mM DMSO stock in HBSS,and incubated at room temperature for 20 minutes. The reaction wasstopped with the addition of 500 μL of methanol containing 20 ng/mLprostaglandin B2 as an internal standard. Samples were collected andstored at −20° C. at least 2 hr or overnight before centrifuged at13,000 rpm for 15 minutes and loaded onto C18 SEP-PAK columns (CanadianLifesciences IS12000) for solid phase extraction. The leukotrienes wereanalyzed by HPLC using an ACE C18 column (4.5 mm×150 mm, 5 μm) elutedwith acetonitrile/methanol/water mixture with H₃PO₄, pH 3.5 (37:26:37)with a flow rate of 1.8 mL/min. The amount of LTB₄ (Cayman Chemical,20110) and LTC₄ (Cayman Chemical, 20210) were calculated based onreference standards and the level of inhibition of LTB₄ productioninduced by the test compounds was calculated relative to controlsamples. The results are provided in Table 2, where Compound No. refersto the compounds identified in Table 1.

TABLE 2 % Inhibition % Inhibition % Inhibition % Inhibition CompoundLTC4 LTB4 LTC4 LTB4 No. (3 μM) (3 μM) (1 μM) (1 μM) 101  <10%  <10% 10210-30%  >90% 103  >90%  >90% 50-70% 50-70% 104  >90%  >90%  >90%  >90%105 70-90% 30-50% 30-50% 106 30-50% 10-30% 10-30% 10-30% 107  >90%  >90%70-90%  >90% 108 50-70%  >90% 70-90%  >90% 109 50-70% 70-90% 110  <10% <10% 111 70-90% 70-90% 115  <10%  >90%  <10%  <10% 116  <10%  <10% 11730-50% 70-90% 119  >90%  >90%  >90%  >90% 120 70-90% 70-90% 121 50-70%50-70% 122 30-50% 30-50% 123 10-30% 50-70% 124 10-30% 126  <10% 10-30%127  <10%  <10% 128  <10%  <10%  <10%  <10% 130  <10% 10-30% 131 50-70% <10% 132 70-90%  >90% 133  <10% 30-50% 134 10-30% 10-30% 135 10-30%30-50% 136 10-30%  <10% 137 50-70% 30-50% 10-30% 138 70-90% 70-90%30-50% 10-30% 139  >90%  >90% 140  <10%  <10% 141 10-30%  >90% 14310-30%  >90% 144 10-30%  >90% 146 10-30%  >90% 147 30-50%  >90% 14930-50% 50-70% 150 70-90%  >90% 10-30% 50-70% 151 10-30% 10-30% 15230-50% 30-50% 30-50% 50-70% 154  <10% 10-30% 30-50% 50-70% 155  <10%10-30% 156  <10%  >90% 157  <10% 70-90% 158  <10%  >90% 10-30%  >90% 15910-30% 30-50% 160  <10% 50-70% 161  <10% 10-30% 162  <10% 70-90% 16310-30% 50-70% 164  <10%  >90% 165  <10% 70-90% 166 30-50% 50-70% 16710-30% 10-30% 10-30% 10-30% 168  <10% 10-30% 170  >90%  >90% 171 70-90%70-90% 173 30-50% 176  <10%  <10% 177 30-50% 178  <10%  <10% 179 10-30%10-30% 180  <10% 10-30% 181  <10% 10-30% 182 10-30% 183  >90%  >90% >90%  >90% 184  >90% 185 70-90%  >90% 186 70-90% 50-70% 187 50-70%50-70% 188 10-30%  <10% 189 70-90%  >90% 190 30-50% 30-50% 191  >90% >90% 193 70-90%  >90%  >90%  >90% 195  >90%  >90% 196  >90%  >90% 197 >90%  >90% 198 30-50% 70-90% 199 30-50% 50-70%

The enantiomers of Compound 104 had divergent potency with respect toinhibiting LTC4 and LTB4. Notably, Enantiomer 1 demonstrated enhanced %inhibition of LTC4 (0.3 μM—74%) compared to Enantiomer 2 (0.3 μM—10%).Also notably, Enantiomer 1 demonstrated enhanced inhibition of LTB4 (0.3μM—83%) compared to enantiomer 2 (0.3 μM—24%).

Notably, Compound 104 demonstrated enhanced % inhibition LTC4 (1 μM)(90%) compared to Compound 103 (50-70%). Also notably, Compound 104demonstrated enhanced % inhibition LTB4 (1 μM) (90%) compared toCompound 103 (50-70%). Structurally, Compounds 103 and 104 differ onlyin the presence of an —S-alkyl substitutent on the Ar ring of compound104, and more specifically a —S—CH₃ group.

Accordingly, in one embodiment, the present disclosure providescompounds of formula (1) having an —S-alkyl substituent on Ar, and morespecifically compounds of formula (1)

and pharmaceutically acceptable salts thereof, wherein: Ar is a 9- or10-membered bicyclic aromatic ring system, where Ar is substituted withone, two or three substituents including at least one —S-alkyl, where—S-alkyl may be —S—C₁-C₆alkyl, e.g., —S-methyl; L is selected from adirect bond and methylene; R¹ is selected from hydrogen, halide,C₁-C₆alkyl, C₁-C₆haloalkyl and C₁-C₆alkoxy; A is selected from a directbond, —CH₂— and —CH₂CH₂—; E is selected from —C(O)—R², C(OR³)R⁴R⁵ andCH(R⁶)NR⁷R⁸; R² is selected from methyl, ethyl and phenyl; R³ isselected from H, alkyl and substituted alkyl; R⁴ is selected fromhydrogen, alkyl and phenyl; R⁵ is selected from C₁-C₇alkyl,C₁-C₇haloalkyl, phenyl and substituted phenyl; R⁶ is selected fromhydrogen, methyl, halogenated methyl and ethyl; R⁷ is hydrogen; and R⁸is hydrogen, methyl or ethyl; with the proviso that together, R⁷ and R⁸may form a 5 or 6-membered, optionally substituted, heterocycle. As tothe Ar group, optionally Ar is a mono-substituted 9-membered bicyclicaromatic ring; or optionally Ar is a di-substituted 9-membered bicyclicaromatic ring; or optionally Ar is a tri-substituted 9-membered bicyclicaromatic ring; or optionally Ar is a mono-substituted 10-memberedbicyclic aromatic ring; or optionally Ar is a di-substituted 10-memberedbicyclic aromatic ring; or optionally Ar is a tri-substituted10-membered bicyclic aromatic ring; or optionally Ar is selected from1,3-benzoxazole and 1,3-benzothiazole; or optionally Ar is naphthaleneor a nitrogen-substituted analog thereof selected from1,5-naphthyridine, 1,6-naphthyridine, 1,7-naphthyridine,1,8-naphthyridine, isoquinoline, phthalazine, 2,6-naphthyridine and2,7-naphthyridine. As to the other substituents, any one or more of thefollowing may be used to further described the compounds of theembodiment: L is a direct bond; L is methylene; R¹ is hydrogen; R¹ ishalogen; R¹ is C₁-C₆alkyl; R¹ is C₁-C₆haloalkyl; R¹ is C₁-C₆alkoxy; A isa direct bond; A is —CH₂—; A is —CH₂CH₂—; E is —C(O)—R²; R² is methyl;R² is ethyl; R² is phenyl; E is —C(OR³)R⁴R⁵; R³ is hydrogen; R³ isalkyl; R³ is substituted alkyl; R⁴ is hydrogen; R⁴ is alkyl; R⁴ isphenyl; R⁵ is C₁-C₇alkyl; R⁵ is C₁-C₇haloalkyl, e.g., R⁵ istrifluoromethyl; R⁵ is phenyl; R⁵ is substituted phenyl; E is—CH(R⁶)NR⁷R³; R⁶ is hydrogen; R⁶ is methyl; R⁶ is halogenated methyl; R⁶is ethyl; R⁸ is hydrogen; R⁸ is methyl; R⁸ is ethyl; R⁷ and R⁸ togetherform a 5 membered heterocycle; R⁷ and R⁸ together form a substituted 5membered heterocycle; R⁷ and R⁸ together form a 6 membered heterocycle;and/or R⁷ and R⁸ together form a substituted 6 membered heterocycle.

Notably, comparing the performance of Compound 103 to Compound 150,Compound 103 demonstrated % Inhibition LTC4 (1 μM) of 50-70% and %Inhibition LTB4 (1 μM) of 50-70%, i.e., there was no detectabledifference in performance. However, Compound 150 demonstrated %Inhibition LTC4 (1 μM) of 10-30% and % Inhibition LTB4 (1 μM) of 50-70%,i.e., there was a detectable difference in performance. Structurally,Compounds 103 and 150 differ only in the presence of an —O-alkylsubstitutent on the benzene ring of compound 103, and more specificallya —O—CH₃ group as the R₁ substituent.

Accordingly, in one embodiment, the present disclosure providescompounds of formula (1) wherein R¹ is O-alkyl, and more specificallycompounds of formula (1)

and pharmaceutically acceptable salts thereof, wherein: Ar is a 9- or10-membered bicyclic aromatic ring system, where Ar is substituted withone, two or three substituents; L is selected from a direct bond andmethylene; R¹ is C₁-C₆alkoxy; A is selected from a direct bond, —CH₂—and —CH₂CH₂—; E is selected from —C(O)—R², C(OR³)R⁴R⁵ and CH(R⁶)NR⁷R³;R² is selected from methyl, ethyl and phenyl; R³ is selected from H,alkyl and substituted alkyl; R⁴ is selected from hydrogen, alkyl andphenyl; R⁵ is selected from C₁-C₇alkyl, C₁-C₇haloalkyl, phenyl andsubstituted phenyl; R⁶ is selected from hydrogen, methyl, halogenatedmethyl and ethyl; R⁷ is hydrogen; and R⁸ is hydrogen, methyl or ethyl;with the proviso that together, R⁷ and R⁸ may form a 5 or 6-membered,optionally substituted, heterocycle. As to the Ar group, optionally Aris an unsubstituted 9-membered bicyclic aromatic ring; or optionally Aris a mono-substituted 9-membered bicyclic aromatic ring; or optionallyAr is a di-substituted 9-membered bicyclic aromatic ring; or optionallyAr is a tri-substituted 9-membered bicyclic aromatic ring; or optionallyAr is an unsubstituted 10-membered bicyclic aromatic ring; or optionallyAr is a mono-substituted 10-membered bicyclic aromatic ring; oroptionally Ar is a di-substituted 10-membered bicyclic aromatic ring; oroptionally Ar is a tri-substituted 10-membered bicyclic aromatic ring;or optionally Ar is selected from 1,3-benzoxazole and 1,3-benzothiazole;or optionally Ar is naphthalene or a nitrogen-substituted analog thereofselected from 1,5-naphthyridine, 1,6-naphthyridine, 1,7-naphthyridine,1,8-naphthyridine, isoquinoline, phthalazine, 2,6-naphthyridine and2,7-naphthyridine. As to the other substituents, any one or more of thefollowing may be used to further described the compounds of theembodiment: L is a direct bond; L is methylene; A is a direct bond; A is—CH₂—; A is —CH₂CH₂—; E is —C(O)—R²; R² is methyl; R² is ethyl; R² isphenyl; E is —C(OR³)R⁴R⁵; R³ is hydrogen; R³ is alkyl; R³ is substitutedalkyl; R⁴ is hydrogen; R⁴ is alkyl; R⁴ is phenyl; R⁵ is C₁-C₇alkyl; R⁵is C₁-C₇haloalkyl, e.g., R⁵ is trifluoromethyl; R⁵ is phenyl; R⁵ issubstituted phenyl; E is —CH(R⁶)NR⁷R⁸; R⁶ is hydrogen; R⁶ is methyl; R⁶is halogenated methyl; R⁶ is ethyl; R⁸ is hydrogen; R⁸ is methyl; R⁸ isethyl; R⁷ and R⁸ together form a 5 membered heterocycle; R⁷ and R⁸together form a substituted 5 membered heterocycle; R⁷ and R⁸ togetherform a 6 membered heterocycle; and/or R⁷ and R⁸ together form asubstituted 6 membered heterocycle.

Example 101 Whole Blood HPLC Assay

Porcine or human whole blood (1 mL) was pre-incubated with a series ofconcentrations of compound solubilized in DMSO for 30 minutes.Production of leukotrienes were stimulated with the addition of 20 μMcalcium ionophore (A23187), diluted from a 4 mM DMSO stock in HBSS, andincubated at room temperature for 20 minutes. In porcine blood 20 μMarachidonic acid was added in addition to the calcium ionophore. Theblood was centrifuged at 2,000 rpm for 15 minutes, and the plasmafraction removed for further processing. Plasma samples were dilutedwith 500 μL acidified water (HCl pH 3.0) and loaded onto C18 SEP-PAKcolumns (Canadian Lifesciences IS12000) for solid phase extraction. Theleukotrienes were analyzed by HPLC using an ACE C18 column (4.5 mm×150mm, 5 μm) eluted with acetonitrile/methanol/water mixture with H₃PO₄, pH3.5 (37:26:37) with a flow rate of 1.8 mL/min. The amount of LTB₄(Cayman Chemical, 20110) was calculated based on reference standards andthe level of inhibition of LTB₄ production induced by the test compoundswas calculated relative to control samples. The results provided inTable 3 are IC₅₀ values calculated based on a 5 point curve, whereCompound No. refers to the compounds identified in Table 1.

TABLE 3 Compound No. Whole Blood IC₅₀ 103 1-10 μM 104 0.1-1 μM 106 >10μM 107 >10 μM 108 1-10 μM 115 >10 μM 117 >10 μM 119 1-10 μM 132 >10 μM137 >10 μM 138 1-10 μM 139 1-10 μM 141 1-10 μM 146 1-10 μM 150 1-10 μM155 >10 μM 156 0.1-1 μM 157 1-10 μM 158 0.1-1 μM 160 >10 μM 163 >10 μM164 0.1-1 μM 166 0.1-1 μM 167 >10 μM 183 0.1-1 μM 184 0.1-1 μM 185 0.1-1μM 197 0.1-1 μM 198 0.1-1 μM 199 >10 μM

Example 1012 Amino-Peptidase Assay—Alanine-4-Nitroanalide

A series of compound concentrations were pre-incubated in the absence oflight with 0.5 μg of recombinant human leukotriene A4 hydrolase enzyme(Cayman Chemical 10007817) in 50 μL assay buffer (50 mM Tris-HCl, 100 mMKCl). The reaction was stimulated by adding 50 μL 6 mMalanine-4-nitroanilide (Sigma Aldrich A9325) in assay buffer. The amountof amino-peptidase activity was measured by determining the change inabsorbance at 405 nm due to 4-nitroanaline production and comparing therate of change to a reference standard (Sigma Aldrich 185310).Amino-peptidase activity was compared to control samples and the levelof inhibition was calculated. Compounds that augment peptidase activityare represented by negative values. The results are shown in Table 4,where Compound No. refers to the compounds listed in Table 1.

Example 1023 Amino-Peptidase Assay—PGP

A series of compound concentrations were pre-incubated with 50 ng ofrecombinant human leukotriene A₄ hydrolase enzyme (Cayman Chemical,10007817) in 50 μL assay buffer (50 mM Tris-HCl, 100 mM KCl). Thereaction was stimulated by adding 50 μL 1 mM proline-glycine-proline(Bachem, H-7284) and incubated for 30 minutes at 37° C. The reaction wasstopped with the addition of 150 μL of glacial acetic acid. The amountof free proline released from the peptide was detected through areaction with ninhydrin. 150 μL of 25 mg/mL ninhydrin (BDH, B10132) in60:40 acetic acid/water was added to each sample, and boiled for 30minutes at 100° C. and once samples had cooled to room temperature, 350μL of toluene was added to extract the ninhydrin reaction product. Theamount of free proline was determined by comparing the absorbance at 520nm to the L-proline (Sigma Aldrich, 81709) reference standard.Inhibition of free proline production was calculated based on controlsamples. The results are shown in Table 4, where Compound No. refers tothe compounds listed in Table 1.

TABLE 4 % Inhibition aminopeptidase- % Inhibition CompoundAlanine-4-nitroanalide activity aminopeptidase-PGP No. of LTA4H (3 μM)activity of LTA4H 102 −0-50%  104 −50-100%     105  75% 109 −0-50%  112 <25% 121 −0-50%  123 25-50%  128 <25% 146 <25% 147 50-75%  25-50% 148<25% 149 <25% 25-50% 150 25-50%   <25% 152 <25% 25-50% 154 >75% 15850-75%  164 >75% 165 50-75%  166 <25% 167 >75% 173 −0-50%  175 50-75% 176 <25% 177 >75% 178 70-90%  70-90% 179 >75%  >75% 180 50-75%  181−0-50%   >75% 182 <25% 183 >75%  >75% 184 <25% 25-50% 186 >75%  >75%187 >75% 50-75% 188 <25% 25-50% 190 <25% 25-50%

Example 104 Arachidonic Acid (AA) Induced Mouse Ear Edema Model

The mouse model of arachidonic acid induced ear edema is an acute modelof inflammation of the skin exhibiting redness and swelling in responseto application of the stimulus to the skin. One group serves as acontrol and receives 20 μL of vehicle applied to the pinna of each ear(10 μL to the inside and 10 μL to the outside of the pinna). One or moreadditional groups serve as test groups. The test compound was applied tothe pinna of one ear of the mouse in a 20 μL volume (10 μL to the insideand 10 μL to the outside of the pinna). Test compound or control vehicle(acetone/1% DMSO) was applied topically to the right ear 4 and 1 hourbefore the application of 2 mg/ear AA as a stimulus to both the innerand outer surfaces of CD-1 mice. The left ears received vehicle(acetone/1% DMSO) alone.

The animal was lightly anesthetized again using isofluorane to enableapplication of the stimulus. For the control group, arachidonic acid (2mg/ear) was applied as the stimulus to the pinna of one ear only, in atotal volume of 20 μL of acetone (10 μL applied to the inside and 10 μLto the outside of the pinna). The other ear received 20 μL of acetone.This served to determine the increase in ear weight due to arachidonicacid in the absence of test compounds. For the test groups, arachidonicacid (2 mg/ear) was applied as the stimulus to the pinna of each ear, ina total volume of 20 μL of acetone (10 μL applied to the inside and 10μL to the outside of the pinna). The animal was allowed to recover afterapplication of the stimulus in each case. After 60 minutes the animalwas euthanized and a standard biopsy sample was taken from each earusing a 6 mm skin biopsy punch (Acuderm). Ear edema was determined bythe increase in weight of the tissue due to accumulation of fluid as aresult of plasma extravasation. The ears were weighed separately using abalance suitable to record 0.1 mg. For the control group, the differencein ear weights was determined by subtracting the weight of theunstimulated ear from the stimulated ear, and this was a measure of theincrease in ear weight due to edema. The percentage increase in earweight was determined by dividing the increase in stimulated ear weightby the unstimulated ear weight and multiplying by 100. For the testgroups, the difference in ear weights was determined by subtracting theweight of the untreated ear from the weight of the ear treated with testcompound. The percent inhibition of the increase in ear weight for earstreated with the test compound was estimated by first subtracting themean ear weight of the untreated controls from each tissue to determinethe increase in tissue weight due to application of the arachidonicacid.

The percent inhibition=1−(test drug stimulated ear (mg)/controlstimulated ear (mg))×100.

In Table 5, the data from inhibition of AA-induced ear edema in mice bytopical application of compounds is provided. Compounds (0.3 or 1mg/ear) were applied topically to the ear 4 hrs and 1 hr prior toapplication of arachidonic acid (AA; 2 mg/ear). Representative data from4-6 mice per treatment group is shown, where Compound No. refers to thecompounds listed in Table 1.

TABLE 5 Compound % Inhibition AA-Induced % Inhibition AA-Induced No. earedema (1 mg/ear) ear edema (0.3 mg/ear) 103 70-90% 30-50% 158 10-30% 10830-50%  <10% 104 50-70% 30-50% 183  >90% 30-50% 119 50-70% 30-50%

Example 1035 Lipopolysaccharide (LPS) Mouse Lung Inflammation Model

In this model, LPS was instilled into the lungs of mice to induce aneutrophilia in the lung tissue. The neutrophilia can be measured in theBAL fluid during lung lavage at various times after challenge with LPS.The neutrophilia develops with a significant increase in cells in theBAL after 6 hrs and achieves a maximum response by 24 hrs.

CD-1 mice received lipopolysaccharide (LPS) 2.5 mg/kg in phosphatebuffered saline (PBS) or PBS in a volume of 50 μL by intrachealinstillation into the lung. The animals were lightly anesthetized usingisofluorane to enable application of the LPS. When anesthetized theanimals were placed on a board at an angle of 45°. The tongue was rolledto one side and LPS was administered directly into the trachea in avolume of 50 μL. The animal remained in position for 1-2 minutes toensure the LPS remained in the lung. At the end of the LPS challengetime, animals were euthanized by an overdose of isofluorane. The tracheawas exposed and the lungs were intubated using a 21G catheter tube. Thelungs were lavaged with 2×1 mL of PBS at room temperature. The recoveredbronchiolar lavage fluid (BAL) was placed on ice and centrifuged at 2500rpm (desktop centrifuge) for 5 min to pellet the recovered cells. TheBAL supernatant was removed and the cell pellet was resuspended in 150μL of PBS. The differential cell counts were determined using anautomated cell counter (Abraxia) set to measure mouse cells. Cellconcentration of the resuspended sample was expressed as total cellsrecovered in the total volume of recovered BAL.

Animals receive test drug or vehicle (polyethylene glycol 200 (PEG200)with 1% DMSO) at doses of 10-30 mg/kg orally at various times prior toand after instillation of LPS. For example, test drug may beadministered 30 minutes prior to LPS, and again 2 hours after LPS, ormay be co-administered with LPS and again 2 hrs and 4 hrs after LPS.

The resulting data is shown in FIG. 1, which shows the effect ofCompound 104 on LPS-induced neutrophil infiltration into the lung.Animals were treated orally with either 10 mg/kg of Compound 104, 1mg/kg Dexamethasone or dosing vehicle (PEG 200 with 1% DMSO) 1 hr beforeand 2 hrs after 2.5 mg/kg LPS was administered intratracheally. Animalswere euthanized 6 hr post-LPS and the BAL was collected from the lung.The results demonstrating inhibitory effect of Compound 104 are shown inFIG. 1, which represent the mean±standard deviation, n=7-10 animals pergroup.

Example 1046 Rat Endotoxin Induced Uveitis (EIU) Model

The endotoxin induced uveitis (EIU) model employs an injection of LPSinto the hind footpad of the rat with assessment of inflammation in theeye 24 hrs later. EIU can be induced by systemic injection oflipopolysaccharide (LPS), which generates inflammatory responses largelyin the anterior uvea and mild responses in the posterior segments of theeye, mimicking the pathological conditions in human acute anterioruveitis.

In general, cellular inflammation in EIU starts 4 hrs after injection ofLPS, with maximum infiltration after 18-24 hrs. Inflammation in the eyeis determined by assessment of the clinical score, and determination ofcell content and protein content in the aqueous and vitreous humor ofthe each eye. Aqueous and vitreous humor from normal control animalshave few detectable cells present, and low levels of protein, withorganized tissues layers under histological examination. In contrast,after LPS the aqueous humor has elevated cell content and proteincontent, extravasation into the anterior space manifested by the abilityto remove a larger volume of fluid for assessment. Similar effects areobserved in the vitreous humor, with a large vitreous humor mass whichis easily extracted for evaluation. Histologically structures within thetissue are less well organized showing evidence of inflammatory cellinfiltrate, large amount of protein matrix in the aqueous humor, anddisorganization and inflammatory cell infiltration associated with theiris-ciliary body.

Rats received an injection of 75 μg LPS, prepared in 100 μL saline, intothe hind footpad to initiate disease. The level of inflammation in theeye was evaluated by assessment of the clinical score which assessesiris hyperemia, pupil dilation, exudate and hypopyon, and determinationof cell content and protein content in the aqueous and vitreous humor ofthe each eye through histological examination of tissue sections.

Animals received test drug or vehicle (PEG 200 with 1% DMSO) at doses of30 mg/kg orally at various times prior to and after injection of LPS.Animals may also receive test drug topically where the test drug wasadministered as a 10 μL drop directly to the eye, using a dose solutionup to 1% test drug in a formulation consisting of 20% hydroxypropylbeta-cyclodextrin, 0.5% hydroxypropyl methyl cellulose and 1.6 mM EDTAin PBS, directly to the eye at various times before and after LPSadministration.

The results for oral dosing of test drug are provided in FIG. 2. FIG. 2shows the effect of Compound 104 on clinical scores in the EIU ratmodel. Animals were treated with 30 mg/kg of Compound 104 or dosingvehicle (PEG 200 with 1% DMSO) orally 15 min before and 5 hrs after 75of LPS from Salmonella Typhimurium in 100 μL saline was administeredsubcutaneously in the hind foot pad of each foot. Mean clinical scoreswere determined at 24 hrs post LPS dose. Values shown in FIG. 2represent the mean±standard deviation, n=3 per group.

Example 10507 Rat Ocular Distribution Model

Eye drops were prepared by adding compounds at a theoreticalconcentration of 10 mg/mL to a 2 mL microcentrifuge tube before adding astir bar and the selected formulation that consisted of (w/v)hydroxypropyl β-cyclodextrin (Trappsol) (20%), hydroxyl propylmethylcellulose (0.5%) and EDTA (1.6 mM) in phosphate buffered saline.Tubes containing compound in eye drop formulation were heated to 60-65°C. and stirred at least 4 hours to overnight. The tubes were removedfrom the heat bath and centrifuged at 10,000 rcf for 5 minutes to clearthe solution of any residual drug not in solution. The supernatant wasremoved from the tubes and one 10 μL sample was removed for HPLCanalysis of solubilized by HPLC using an ACE C18 column (4.5 mm×150 mm,5 μm), eluted with acetonitrile/methanol/water mixture with H₃PO₄, pH3.5 (50:30:20) with a flow rate of 2.5 mL/min. The solubilizedconcentration of each compound was calculated by interpolation from astandard curve based on reference standards solubilized in methanol whenthe assay was validated.

Compounds were applied as a single 10 μL drop to rats and the aqueoushumor, and the posterior segment of the eye (vitreous body and retina)were collected from each eye at the time point assigned after the eyewas irrigated to remove any residual formulation present. Tissues werecollected in pre-weighed collection tubes and the tissue weight wasdetermined for each sample. An internal standard (IS) mixture containinga reference compound at a ratio of 14 to 4 mg tissue was added tosamples, mixed and then diluted ×4.25 in acetonitrile:methanol (9:1).Aqueous humour samples were vortex mixed for 10 s. The vitreous body &retina were vortex mixed 2 times each for 10 s, and further mixed for 6min on a tabletop shaker at 750 rpm followed by final vortex mixing (10s). All samples were centrifuged to pellet any particulate matter andthe supernatant was transferred to LC vials. A 10 μL sample was thenapplied to the HPLC during LC/MS/MS analysis. A calibration curve forcompounds (0.588-176.471 ng/mL) was prepared in rat plasma to estimateconcentrations of compounds in each of the matrices analyzed using thearea under curve (AUC) normalized to internal standard AUC fordetermining response. The assumption was made that 1 mg tissue isequivalent to 1 μL plasma. Concentrations measured in each tissue werethen normalized to the amount of drug applied to account for differencesin solubilized drug in each formulation. The average concentration andthe standard deviation was determined based on “n”=number of eyesassessed, rather than the number of animals.

In Table 6, the data from distribution studies performed in Lewis ratsshow the concentration of each compound present in the retina 0.5 hrafter the administration of a 10 μL drop of each topical formation isprovided. Compounds were paired and individual formulations mixed at aratio to make a mixture that contained ^(˜)2.5 mg/mL of each compound.Representative data from 2 eyes is shown, where Compound No. refers tothe compounds listed in Table 1.

TABLE 6 Concentration of compound Concentration in retina 0.5 hr afterof compound in administration (ng/mL) per Compound formulation mgcompound applied No. (ng/mL) (Avg ± SD) n = 2 104 2.86 3340 ± 1061 1911.65 4872 ± 1672 193 2.53 15690 ± 9863  195 3.64  3343 ± 2.4  

In another study, Sprague Dawley rats received a 10 μL drop of eitherCompound 104 (0.4%) or commercially available ophthalmic prednisoloneacetate (1%) and tissues were removed 2 hours post administration tomeasure compound concentration by LC/MS/MS. The resulting data in FIG.3, which represent the mean±standard deviation, n=5 eyes per drug, showsthat Compound 104 was absorbed into the posterior segment at levels 50×that of prednisolone 2 hours after administration.

Example 10608 Rat Experimental Autoimmune Uveitis (EAU) Model

Experimental autoimmune uveitis is an organ specific T-cell mediatedautoimmune disease that targets neural retinal and related tissues thatis induced by immunization with retinal antigens. Histologically itinvolves inflammatory cell infiltration of the retina leading tophotoreceptor damage, extending to the inner nuclear layer, leading toedema and retinal detachment at the peak of severity. In additional tochanges in the eye posteriorly, inflammatory cell infiltration isprominent in the anterior segment of the eye, with vascular engorgement,loss of red reflex, and haziness in anterior chamber.

The experimental autoimmune uveitis (EAU) model is initiated byinjection of Complete Freund's Adjuvant (CFA) containing a heat killedform of a laboratory strain of tuberculosis bacteria and a peptidedirected towards toward a retinal protein that causes inflammation inthe eye in susceptible animals such as the Lewis rat. At approximately6-7 days after injection of the CFA and retinal protein, clinical signsof ocular inflammation are visible, which peak at approximately 10-14days, and are mostly resolved within 21 days.

Lewis rats were injected with an emulsion of retinal peptide (<100 rig)and Complete Freund's Adjuvant (2-3 mg/ml) subcutaneously with 100 μLinjection at the base of the tail and an additional 50 μL in each thigh.This was undertaken in a biological safety cabinet, and throughout thestudy the animals remain in containment housing. The animal was lightlyanesthetized using isofluorane to enable administration of the stimulus.Starting at day 6-8 after immunization, rats were lightly anesthetizedusing isofluorane to enable administration of the dose of test drug as10 μL drop directly to the eye, using a dose solution up to 1% test drugin a formulation consisting of 20% hydroxypropyl beta-cyclodextrin, 0.5%hydroxypropyl methyl cellulose and 1.6 mM EDTA in PBS, and continue tobe treated as the disease develops over several days. Disease symptomswere scored to assess blood vessel dilation, engorgement of bloodvessels, change in red reflex and haziness of anterior chamber andproptosis (scale 0-4) (Agarwal et al Autoimmunity: Methods andProtocols, Methods in Molecular Biology, vol. 900, Ch 22). Animals wereeuthanized by isoflurane and CO₂ and the eye excised and evaluatedhistologically for structural changes and inflammatory cell infiltratewithin the eye and scored based on pathological changes (Gadjanski etal. Experimental Eye Research 93 (2011) 82e90). Retinal thicknessmeasurements were performed on histological sections using AperioImageScope (Leica Biosystems) from the retinal pigment epithelial layerto the internal limiting membrane.

The results from this example are shown in FIG. 4A, FIG. 4B and FIG. 4C.In these figures, the effect of Compound 104 on clinical scores andhistological evaluation in the EAU rat model is shown. Animals wereimmunized with 30 μg of peptide in an emulsion containing 2 mg/mLComplete Freunds Adjuvant on day 0. From day 6 post immunization,animals received 10 μL of 0.5% wt/vol Compound 104 or vehicle (liquidformulation containing of 20% hydroxypropyl beta-cyclodextrin, 0.5%hydroxypropyl methyl cellulose and 1.6 mM EDTA in PBS) topically in eacheye every 3 hours for four doses each day, and once orally (30 mg/kg)immediately after the last topical dose each day. Animals were treateddaily until euthanized 10 days post-immunization and tissues collectedfor histological examination. Values represent the mean±standarddeviation of 4 eyes, n=2 per group. FIG. 4A shows the mean clinicalscores which were determined at various times post immunization. FIG. 4Bshows histological scores which were obtained 10 days post immunization.FIG. 4C shows the results of retinal thickness measurements which weredetermined from histological slides 10 days post immunization.

For selected compounds prepared according to the previous examples, ¹Hnuclear magnetic resonance spectroscopy was performed to obtain ¹H NMRspectra, which are characterized as described and provided in Table 7.

TABLE 7 Compound No. NMR data 101 ¹H NMR (300 MHz, CDCl₃): δ 7.74 (d,1H), 7.64 (d, 1H), 7.44-7.18 (m, 3H), 6.93- 6.79 (m, 2H), 3.80 (s, 3H),2.94 (t, 2H), 2.78 (t, 2H), 2.45 (q, 2H), 1.07 (t, 3H). 103 ¹H NMR (300MHz, CDCl₃): δ 7.75 (d, 1H), 7.64 (d, 1H), 7.46-7.20 (m, 3H), 6.93- 6.82(m, 2H), 3.81 (s, 3H), 2.83-2.71 (m, 2H), 2.12-1.97 (m, 2H), 1.85 (q,2H), 1.05 (t, 3H). 104 ¹H NMR (300 MHz, CDCl₃): δ 7.44-7.37 (m, 1H),7.26 (d, 1H), 7.23-7.16 (m, 2H), 6.88-6.80 (m, 2H), 3.82 (s, 3H), 2.77(t, 2H), 2.55 (s, 3H), 2.08-1.97 (m, 2H), 1.94 (s, 1H), 1.90-1.78 (m,2H), 1.06 (t, 3H). 105 ¹H NMR (300 MHz, CDCl₃): δ 7.55-7.50 (m, 1H),7.27 (d, 1H), 7.24-7.20 (m, 1H), 7.19-7.14 (m, 2H), 6.86-6.80 (m, 2H),3.78 (s, 3H), 3.75 (s, 3H), 2.74 (t, 2H), 2.08- 1.95 (m, 3H), 1.90-1.76(m, 2H), 1.05 (t, 3H). 106 ¹H NMR (400 MHz, CDCl₃): δ 8.28 (d, 1H), 7.92(dd, 1H), 7.85 (d, 1H), 7.24 (d, 1H), 6.91-6.85 (m, 2H), 3.82 (s, 3H),3.08 (s, 3H), 2.78 (t, 2H), 2.08-2.00 (m, 2H), 1.97 (s, 1H), 1.91-1.79(m, 2H), 1.06 (t, 3H). 107 ¹H NMR (400 MHz, CDCl₃): δ 7.24 (d, 1H),7.18-7.13 (m, 1H), 6.94-6.82 (m, 3H), 3.82 (s, 3H), 2.77 (t, 2H),2.06-1.98 (m, 2H), 1.95 (s, 1H), 1.89-1.80 (m, 2H), 1.06 (t, 3H). 108 ¹HNMR (300 MHz, CDCl₃): δ 7.66 (dd, 1H), 7.34 (dd, 1H), 7.30-7.20 (m, 1H),7.16- 7.05 (m, 1H), 6.93-6.82 (m, 2H), 3.82 (s, 3H), 2.83-2.72 (m, 2H),2.04-1.79 (m, 5H), 1.06 (t, 3H). 111 ¹H NMR (400 MHz, CDCl₃): δ 7.72 (d,1H), 7.64 (d, 1H), 7.39-7.33 (m, 1H), 7.27- 7.21 (m, 2H), 6.89-6.82 (m,2H), 3.82 (s, 3H), 2.90-2.73 (m, 2H), 2.12-1.94 (m, 3H), 1.45 (s, 3H).115 ¹H NMR (400 MHz, CDCl₃): δ 7.71 (d, 1H), 7.64 (d, 1H), 7.39-7.34 (m,1H), 7.27- 7.21 (m, 2H), 6.89-6.81 (m, 2H), 4.58-4.48 (m, 1H), 2.74 (t,2H), 2.07-1.97 (m, 2H), 1.95 (s, 1H), 1.92-1.78 (m, 2H), 1.21 (d, 6H),1.05 (t, 3H). 116 ¹H NMR (400 MHz, CDCl₃): δ 7.70 (d, 1H), 7.64 (d, 1H),7.38-7.33 (m, 1H), 7.27- 7.19 (m, 2H), 6.86-6.78 (m, 2H), 4.78 (p, 1H),2.74 (t, 2H), 2.06-1.99 (m, 2H), 1.95 (s, 1H), 1.87-1.80 (m, 2H),1.78-1.70 (m, 4H), 1.52-1.39 (m, 4H), 1.05 (t, 3H). 117 ¹H NMR (400 MHz,CDCl₃): δ 7.71 (d, 1H), 7.64 (d, 1H), 7.39-7.33 (m, 1H), 7.27- 7.20 (m,2H), 6.87-6.81 (m, 2H), 3.83 (d, 2H), 2.74 (t, 2H), 2.05-1.98 (m, 2H),1.95 (s, 1H), 1.88-1.80 (m, 2H), 1.05 (t, 4H), 0.43-0.36 (m, 2H),0.15-0.10 (m, 2H). 119 ¹H NMR (400 MHz, CDCl₃): δ 7.44-7.38 (m, 1H),7.26 (d, 1H), 7.22-7.17 (m, 2H), 6.90-6.82 (m, 2H), 3.82 (s, 3H),2.87-2.76 (m, 2H), 2.54 (s, 3H), 2.08-1.94 (m, 3H), 1.46 (s, 3H). 121 ¹HNMR (300 MHz, CDCl₃): δ 7.76 (d, 1H), 7.64 (d, 1H), 7.39 (t, 1H),7.32-7.19 (m, 2H), 6.92-6.80 (m, 2H), 4.05 (q, 2H), 2.82-2.70 (m, 2H),2.50 (broad s, 1H), 2.11- 1.97 (m, 2H), 1.92-1.78 (m, 2H), 1.23 (t, 3H),1.05 (t, 3H). 122 ¹H NMR (300 MHz, CDCl₃): δ 7.75 (d, 1H), 7.64 (d, 1H),7.48-7.19 (m, 3H), 7.01- 6.82 (m, 2H), 3.98-3.78 (m, 1H), 3.80 (s, 3H),2.92-2.64 (m, 2H), 2.00-1.75 (m, 3H), 1.27 (d, 3H). 123 ¹H NMR (300 MHz,CDCl₃): δ 7.74 (d, 1H), 7.63 (d, 1H), 7.55-7.14 (m, 8H), 6.85- 6.72 (m,2H), 3.77 (s, 3H), 2.77-2.40 (m, 2H), 2.27-2.12 (m, 2H), 2.01 (broad s,1H), 1.65 (s, 3H). 124 ¹H NMR (300 MHz, CDCl₃): δ 7.74 (d, 1H), 7.64 (d,1H), 7.38 (t, 1H), 7.31-7.19 (m, 2H), 6.95-6.81 (m, 2H), 3.81 (s, 3H),2.86-2.69 (m, 2H), 1.93-1.73 (m, 3H), 1.32 (s, 6H). 126 ¹H NMR (300 MHz,CDCl₃): δ 7.51 (d, 1H), 7.41 (d, 1H), 7.32-7.17 (m, 3H), 6.92- 6.82 (m,2H), 3.81 (s, 3H), 2.79-2.68 (m, 2H), 1.88-1.66 (m, 3H), 1.32 (s, 6H).127 ¹H NMR (300 MHz, CDCl₃): δ 7.50 (d, 1H), 7.41 (d, 1H), 7.33-7.16 (m,3H), 6.95- 6.80 (m, 2H), 3.81 (s, 3H), 2.77-2.66 (m, 2H), 1.86-1.73 (m,2H), 1.58 (q, 2H), 1.25 (s, 3H), 0.96 (t, 3H). 128 ¹H NMR (300 MHz,CDCl₃): δ 7.61-7.16 (m, 10H), 6.85-6.73 (m, 2H), 3.77 (s, 3H), 2.75-2.38(m, 2H), 2.30-2.01 (m, 3H), 1.64 (s, 3H). 129 ¹H NMR (300 MHz, CDCl₃): δ7.98 (d, 2H), 7.81-7.20 (m, 8H), 6.98-6.84 (m, 2H), 4.04 (q, 2H), 3.34(t, 2H), 3.09 (t, 2H), 1.23 (t, 3H). 130 ¹H NMR (300 MHz, CDCl₃): δ 7.75(s, 1H), 7.68-7.57 (m, 3H), 7.53-7.34 (m, 4H), 7.32-7.16 (m, 2H),6.82-6.71 (m, 2H), 4.00 (q, 2H), 2.80-2.33 (m, 5H), 1.21 (t, 3H). 132 ¹HNMR (300 MHz, CDCl₃): δ 7.76 (d, 1H), 7.64 (d, 1H), 7.51-7.17 (m, 8H),6.97- 6.80 (m, 2H), 4.83-4.70 (m, 1H), 3.79 (s, 3H), 2.95-2.64 (m, 2H),2.35-2.06 (m, 3H). 133 ¹H NMR (300 MHz, CDCl₃): δ 7.79 (d, 1H),7.67-7.59 (m, 3H), 7.49-7.24 (complex m), 7.19 (d, 1H), 6.79-6.73 (m,2H), 3.78 (s, 3H), 2.77-2.69 (m, 1H), 2.59-2.51 (m, 1H), 2.42-2.36 (m,2H). 134 ¹H NMR (400 MHz, CDCl₃): δ 7.71 (d, 1H), 7.64 (d, 1H),7.40-7.27 (m, 6H), 7.26- 7.20 (m, 1H), 7.18 (d, 1H), 6.76-6.71 (m, 2H),3.76 (s, 3H), 3.24-3.14 (m, 1H), 2.58 (broad s, 2H), 2.48-2.06 (m, 6H),1.83-1.69 (m, 4H). 136 ¹H NMR (400 MHz, CDCl₃): δ 12.8 (broad s, 1H),7.70 (d, 1H), 7.64 (d, 1H), 7.39- 7.33 (m, 1H), 7.27-7.19 (m, 2H), 7.00(s, 1H), 6.85 (dd, 1H), 4.56-4.40 (m, 2H), 4.02-3.92 (m, 2H), 3.84 (s,3H), 3.37-3.23 (m, 2H), 3.08-2.79 (m, 5H), 2.52-2.39 (m, 1H), 2.15-1.94(m, 2H), 1.86-1.69 (m, 1H), 1.16 (t, 3H). 137 ¹H NMR (400 MHz, CDCl₃): δ7.72 (d, 1H), 7.67 (d, 1H), 7.41-7.32 (m, 2H), 7.30- 7.23 (m, 1H), 7.20(s, 1H), 7.09 (d, 1H), 5.03-4.96 (m, 1H), 3.84 (s, 3H), 3.10 (d, 1H).138 ¹H NMR (400 MHz, DMSO-d₆): δ 7.91 (d, 1H), 7.67 (d, 1H), 7.45 (d,1H), 7.43-7.38 (m, 2H), 7.34-7.28 (m, 1H), 7.18 (d, 1H), 4.51-4.41 (m,1H), 3.79 (s, 3H), 2.94-2.85 (m, 1H), 2.58-2.48 (m, 1H), 1.04 (t, 3H).139 ¹H NMR (400 MHz, CDCl₃): δ 7.44 (dd, 1H), 7.40 (d, 1H), 7.23-7.18(m, 3H), 7.10 (d, 1H), 5.12-5.04 (m, 1H), 3.85 (s, 3H), 2.76 (d, 1H),2.53 (s, 3H). 140 ¹H NMR (300 MHz, CDCl₃): δ 7.74 (d, 1H), 6.67 (s, 1H),7.47-7.23 (m, 6H), 2.95- 2.70 (m, 2H), 2.16-1.93 (m, 2H), 1.46 (s, 3H).141 ¹H NMR (300 MHz, CDCl₃): δ 7.75 (d, 1H), 7.66 (d, 1H), 7.48-7.13 (m,6H), 3.95- 3.78 (m, 1H), 2.91-2.63 (m, 2H), 1.92-1.74 (m, 2H), 1.26 (d,3H). 142 ¹H NMR (300 MHz, CDCl₃): δ 7.75 (d, 1H), 7.66 (d, 1H),7.45-7.23 (m, 6H), 2.86- 2.65 (m, 2H), 1.93-1.74 (m, 3H), 1.18 (s, 3H),1.07-0.89 (m, 6H). 143 ¹H NMR (300 MHz, CDCl₃): δ 7.75 (d, 1H), 7.66 (d,1H), 7.45-7.09 (m, 6H), 2.82- 2.65 (m, 2H), 1.90-1.73 (m, 2H), 1.69-1.51(m, 3H), 1.24 (s, 3H), 0.952 (t, 3H). 144 ¹H NMR (300 MHz, CDCl₃): δ7.74 (d, 1H), 7.65 (s, 1H), 7.56-7.10 (m, 11H), 2.75- 2.40 (m, 2H),2.24-2.06 (m, 3H), 1.64 (s, 3H). 145 ¹H NMR (300 MHz, CDCl₃): δ 7.74 (d,1H), 7.66 (d, 1H), 7.66 (d, 1H), 7.55-6.99 (m, 10H), 2.73-2.38 (m, 2H),2.22-2.08 (m, 2H), 1.63 (s, 3H). 146 ¹H NMR (300 MHz, CDCl₃): δ7.67-7.21 (m, 8H), 2.81-2.66 (m, 2H), 1.88-1.67 (m, 3H), 1.58 (q, 2H),1.24 (s, 3H), 0.95 (t, 3H). 147 ¹H NMR (300 MHz, CDCl₃): δ 7.63-7.11 (m,13H), 2.74-2.60 (m, 1H), 2.53-2.40 (m, 1H), 2.22-2.08 (m, 2H), 1.64 (s,3H). 148 ¹HNMR (300 MHz, CDCl₃): δ 7.72 (d, 1H), 7.64 (d, 1H), 7.46-7.19(m, 6H), 3.02- 2.88 (m, 2H), 2.83-2.70 (m, 2H), 2.51-2.36 (m, 2H),1.13-1.00 (m, 3H). 149 ¹H NMR (400 MHz, CDCl₃): δ 7.71 (d, 1H), 7.68 (d,1H), 7.42-7.32 (m, 3H), 7.28 (d, 1H), 7.18 (dd, 1H), 2.93 (t, 2H), 2.77(t, 2H), 2.44 (q, 2H), 1.08 (t, 3H). 150 ¹H NMR (300 MHz, CDCl₃): δ 7.75(d, 1H), 7.67 (d, 1H), 7.49-7.24 (m, 6H), 2.77 (t, 2H), 2.13 (broad s,1H), 2.08-1.97 (m, 2H), 1.92-1.78 (m, 2H), 1.05 (t, 3H). 151 ¹H NMR (400MHz, CDCl₃): δ 7.72 (d, 1H), 7.68 (d, 1H), 7.41-7.33 (m, 3H), 7.30- 7.25(m, 1H), 7.19 (dd, 1H), 2.80-2.73 (m, 2H), 2.04-1.98 (m, 2H), 1.94 (s,1H), 1.90-1.78 (m, 2H), 1.05 (t, 3H). 154 ¹H NMR (400 MHz, DMSO-d₆): δ7.96 (d, 1H), 7.68 (d, 1H), 7.53 (t, 1H), 7.46-7.31 (m, 3H), 7.20 (d,1H), 5.82 (s, 1H), 2.72 (t, 2H), 1.99-1.63 (m, 4H), 0.95 (t, 3H). 158 ¹HNMR (400 MHz, CDCl₃): δ 7.73 (d, 1H), 7.66 (d, 1H), 7.43-7.33 (m, 1H),7.33- 7.12 (m, 5H), 3.05-2.38 (m, 7H), 2.09-1.52 (m, 8H), 1.01 (t, 3H).160 ¹H NMR (400 MHz, CDCl₃): δ 7.74 (d, 1H), 7.68 (d, 1H), 7.47 (d, 2H),7.43-7.32 (m, 3H), 7.31-7.25 (m, 1H), 4.96 (q, 1H), 1.85 (s, 1H), 1.53(d, 3H). 161 ¹H NMR (400 MHz, CDCl₃): δ 7.75 (d, 1H), 7.67 (d, 1H), 7.52(d, 2H), 7.43-7.36 (m, 1H), 7.33 (d, 2H), 7.30-7.24 (m, 1H), 1.92-1.80(m, 2H), 1.74 (broad s, 1H), 1.58 (s, 3H), 0.843 (t, 3H). 163 ¹H NMR(400 MHz, CDCl₃): δ 7.75 (d, 1H), 7.72-7.64 (m, 3H), 7.46-7.36 (m, 3H),7.29 (t, 1H), 2.45 (broad s, 1H), 1.82 (s, 3H). 164 ¹H NMR (400 MHz,CDCl₃): δ 7.74 (d, 1H), 7.67 (d, 1H), 7.53 (d, 2H), 7.44-7.32 (m, 3H),7.31-7.23 (m, 1H), 3.82 (s, 2H), 2.76 (broad s, 4H), 2.00-1.83 (m, 4H).165 ¹H NMR (400 MHz, CDCl₃): δ 8.00-7.52 (m, 4H), 7.50-7.08 (m, 4H),4.44 (broad s, 2H), 4.06 (broad s, 1H), 3.72 (broad s, 1H), 3.07 (broads, 1H), 2.54-1.86 (m, 4H). 166 ¹H NMR (400 MHz, CDCl₃): δ 7.74 (d, 1H),7.70 (s, 1H), 7.57 (d, 2H), 7.46-7.36 (m, 3H), 7.30 (t, 1H), 5.09-5.01(m, 1H), 2.88 (d, 1H). 167 ¹H NMR (400 MHz, CDCl₃): δ 7.75-7.68 (m, 2H),7.66 (s, 1H), 7.54-7.36 (m, 3H), 7.34-7.28 (m, 1H), 5.05-4.96 (m, 1H),3.14 (d, 1H). 168 ¹H NMR (400 MHz, CDCl₃): δ 7.75 (d, 1H), 7.69 (d, 1H),7.50 (d, 2H), 7.45-7.37 (m, 3H), 7.32-7.26 (m, 1H), 4.19 (q, 1H), 2.65(q, 2H), 1.13 (t, 3H). 170 ¹H NMR (400 MHz, CDCl₃): δ 7.77 (d, 1H),7.57-7.51 (m, 3H), 7.12 (dd, 1H), 7.04 (d, 2H), 2.83 (s, 3H), 2.52 (d,1H), 1.78 (s, 3H). 171 ¹H NMR (400 MHz, CDCl₃): δ 7.74 (d, 1H), 7.53 (d,1H), 7.36 (d, 2H), 7.10 (dd, 1H), 7.02 (d, 2H), 4.91 (q, 1H), 2.82 (s,3H), 1.79 (broad s, 1H), 1.51 (d, 3H). 173 ¹H NMR (400 MHz, CDCl₃): δ7.72 (d, 1H), 7.66 (d, 1H), 7.41-7.31 (m, 3H), 7.29- 7.22 (m, 1H), 7.18(d, 1H), 3.85 (s, 3H), 2.50 (s, 1H), 1.82 (s, 3H). 183 ¹H NMR (400 MHz,CDCl₃): δ 8.36-8.17 (m, 2H), 7.88 (d, 1H), 7.84-7.70 (m, 2H), 7.61 (t,1H), 7.12 (d, 2H), 6.97 (d, 2H), 5.48 (s, 2H), 2.79-2.63 (m, 2H),2.04-1.85 (m, 3H), 1.42 (s, 3H). 184 ¹H NMR (400 MHz, CDCl₃): δ 8.17 (d,1H), 8.08 (d, 1H), 7.81 (d, 1H), 7.76-7.68 (m, 2H), 7.54 (t, 1H), 6.84(d, 1H), 6.76 (d, 1H), 6.65 (dd, 1H), 5.44 (s, 2H), 3.93 (s, 3H),2.78-2.62 (m, 2H), 2.04-1.85 (m, 3H), 1.42 (s, 3H). 185 ¹H NMR (400 MHz,CDCl₃): δ 8.18 (d, 1H), 8.08 (d, 1H), 7.83 (d, 1H), 7.71-7.71 (m, 1H),7.67 (d, 1H), 7.55 (t, 1H), 7.11 (d, 2H), 6.96 (d, 2H), 5.37 (s, 2H),2.66 (t, 2H), 1.99-1.91 (m, 2H), 1.89 (broad s, 1H), 1.85-1.76 (m, 2H),1.02 (t, 3H). 191 ¹H NMR (400 MHz, CDCl₃): δ [7.93 (dd), 7.75 (dd), 7.48(t), 7.43-7.38 (m), 2H], 7.24-7.17 (m, 2H), 6.90-6.81 (m, 2H), 3.81 (s,3H), [2.95 (s), 2.55 (s), 3H], 2.78- 2.68 (m, 2H), 1.84-1.76 (m, 2H),1.62-1.55 (m, 2H), [1.26 (s), 1.25 (s), 3H], 1.00- 0.93 (m, 3H). 193 ¹HNMR (400 MHz, CDCl3): δ [7.92 (dd), 7.75 (dd), 7.48 (t), 7.44-7.38 (m),2H], 7.25-7.17 (m, 2H), 6.92-6.81 (m, 2H), 3.81 (s, 3H), 3.64-3.55 (m,1H), [2.94 (s), 2.56 (s), 3H], 2.90-2.80 (m, 1H), 2.77-2.66 (m, 1H),1.90-1.72 (m, 2H), 1.62-1.45 (m, 2H), 1.02-0.94 (m, 3H). ¹H NMR (400MHz, DMSO-d6): δ 7.63 (d, 1H), 7.32 (d, 1H), 7.28 (t, 1H), 7.25-7.21 (m,1H), 7.10 (d, 1H), 6.89 (dd, 1H), 4.45 (br s, 1H), 3.77 (s, 3H),2.82-2.72 (m, 1H), 2.68-2.58 (m, 1H), 2.49 9s, 3H), 1.76-1.55 (m, 2H),1.49-1.31 (m, 2H), 0.88 (t, 3H). 195 ¹H NMR (400 MHz, CDCl3): δ [7.94(d), 7.78 (d), 7.50 (t), 7.44 (dd), 2H], 7.36-7.20 (m, 5H), [2.93 (s),2.56 (s), 3H], 2.84-2.72 (m, 2H), 2.08-1.96 (m, 2H), 1.91-1.79 (m, 2H),1.10-1.01 (m, 3H). 196 ¹H NMR (400 MHz, CDCl3): δ 7.79 (d, 1H), 7.64 (d,1H), 7.39 (t, 1H), 7.29-7.24 (m, 1H), 7.22 (d, 1H), 6.90 9d, 1H), 6.86(dd, 1H), 3.81 (s, 3H), 3.64-3.56 (m, 1H), 2.90- 2.80 (m, 1H), 2.76-2.67(m, 1H), 1.89-1.71 (m, 2H), 1.63-1.46 (m, 2H), 0.98 (t, 3H). 197 ¹H NMR(400 MHz, CDCl₃): δ 8.28 (d, 1H), 8.21 (broad s, 1H), 7.87 (d, 1H), 7.79(t, 1H), 7.73 (d, 1H), 7.60 (t, 1H), 7.50 (d, 2H), 7.05 (d, 2H), 5.47(s, 2H), 1.76 (s, 3H). 198 ¹H NMR (400 MHz, CDCl₃): δ 8.36-8.16 (m, 2H),7.90-7.72 (m, 3H), 7.61 (t, 1H), 6.88 (d, 1H), 6.76 (d, 1H), 6.66 (dd,1H), 5.55 (s, 2H), 3.92 (s, 3H), 2.66 (t, 2H), 1.99-1.92 (m, 2H),1.85-1.76 (m, 2H), 1.02 (t, 3H). 199 ¹H NMR (400 MHz, CDCl₃): δ 8.33 (brs, 2H), 7.93-7.77 (m, 3H), 7.63 (t, 1H), 7.20 (s, 1H), 7.03-6.93 (m,2H), 5.60 (s, 2H), 3.94 (s, 3H), 1.75 (s, 3H).

Although any methods and materials similar or equivalent to thosedescribed herein can also be used in the practice or testing of thepresent invention, a limited number of the exemplary methods andmaterials are described herein. Generally, unless otherwise indicated,the materials for making the invention and/or its components may beselected from appropriate starting materials.

Where a range of values is provided herein, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range is encompassed within the disclosure. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges is also encompassed within the disclosure, subject to anyspecifically excluded limit in the stated range. Where the stated rangeincludes one or both of the limits, ranges excluding either or both ofthose included limits are also included in the disclosure.

For example, any concentration range, percentage range, ratio range, orinteger range provided herein is to be understood to include the valueof any integer within the recited range and, when appropriate, fractionsthereof (such as one tenth and one hundredth of an integer), unlessotherwise indicated. Also, any number range recited herein relating toany physical feature, such as polymer subunits, size or thickness, areto be understood to include any integer within the recited range, unlessotherwise indicated. As used herein, the term “about” means±20% of theindicated range, value, or structure, unless otherwise indicated.

All of the U.S. patents, U.S. patent application publications, U.S.patent applications, foreign patents, foreign patent applications andnon-patent publications referred to in this specification and/or listedin the Application Data Sheet are incorporated herein by reference, intheir entirety. Such documents may be incorporated by reference for thepurpose of describing and disclosing, for example, materials andmethodologies described in the publications, which might be used inconnection with the presently described invention. The publicationsdiscussed above and throughout the text are provided solely for theirdisclosure prior to the filing date of the present application. Nothingherein is to be construed as an admission that the inventors are notentitled to antedate any referenced publication by virtue of priorinvention.

In general, in the following claims, the terms used should not beconstrued to limit the claims to the specific embodiments disclosed inthe specification and the claims, but should be construed to include allpossible embodiments along with the full scope of equivalents to whichsuch claims are entitled. Accordingly, the claims are not limited by thedisclosure.

1. A compound of formula (1)

or a pharmaceutically acceptable enantiomer, diastereomer, salt, orsolvate thereof, wherein: Ar is unsubstituted or is substituted with oneor two substituents selected from halide, C₁₋₆alkyl; —S—C₁₋₆alkyl;—O—C₁₋₆alkyl; and —SO₂—C₁₋₆alkyl; L is selected from a direct bond and—CH₂— (methylene); R¹ is selected from hydrogen, halide, C₁-C₆alkyl,C₁-C₆haloalkyl and C₁-C₆alkoxy; A is selected from a direct bond, —CH₂—and —CH₂CH₂—; E is selected from —C(O)—R², C(OR³)R⁴R⁵ and CH(R⁶)NR⁷R⁸;R² is selected from methyl, ethyl and phenyl; R³ is H; R⁴ is selectedfrom hydrogen, C₁-C₇alkyl and phenyl; R⁵ is selected from C₁-C₇alkyl,C₁-C₇haloalkyl, phenyl and halophenyl; R⁶ is selected from hydrogen,methyl, halogenated methyl and ethyl; and R⁷ is hydrogen and R⁸ ishydrogen, methyl or ethyl; or R⁷ and R⁸ together form a 5- or 6-memberedheterocycle which is optionally substituted with a substituent selectedfrom C₁-C₆alkyl and carboxylic acid.
 2. The compound of claim 1 whereinAr is unsubstituted.
 3. The compound of claim 1 wherein Ar issubstituted with a single substituent.
 4. The compound of claim 1wherein Ar is substituted with a single substituent which is —S—CH₃. 5.The compound of claim 1 wherein L is a direct bond.
 6. The compound ofclaim 1 wherein L is methylene.
 7. The compound of claim 1 wherein R¹ ishydrogen or C₁-C₆alkoxy.
 8. The compound of claim 1 wherein A is adirect bond.
 9. The compound of claim 1 wherein A is —CH₂CH₂—.
 10. Thecompound of claim 1 wherein E is —C(OR³)R⁴R⁵ where R³ is H, R⁴ isC₁-C₂alkyl, and R⁵ is trifluoromethyl.
 11. The compound of claim 1 as apure enantiomer or as a non-racemic mixture of enantiomers of compoundsof formula (1).
 12. The compound of claim 1 selected from:1-[4-(1,3-benzothiazol-2-yloxy)-3-methoxyphenyl]-3-(trifluoromethyl)pentan-3-ol;1-{3-methoxy-4-[(4-methylsulfanyl-1,3-benzothiazol-2-yl)oxy]phenyl}-3-(trifluoromethyl)pentan-3-ol;1-{4-[(4,6-difluoro-1,3-benzothiazol-2-yl)oxy]-3-methoxyphenyl}-3-(trifluoromethyl)pentan-3-ol;1-{4-[(6-fluoro-1,3-benzothiazol-2-yl)oxy]-3-methoxyphenyl}-3-(trifluoromethyl)pentan-3-ol;4-[4-(1,3-benzothiazol-2-yloxy)-3-methoxyphenyl]-1,1,1-trifluoro-2-methylbutan-2-ol;1,1,1-trifluoro-4-(3-methoxy-4-{[4-(methylsulfanyl)-1,3-benzothiazol-2-yl]oxy}phenyl)-2-methylbutan-2-ol;1-(3-methoxy-4-{[4-(methylsulfanyl)-1,3-benzothiazol-2-yl]oxy}phenyl)pentan-3-ol;and1-(4-{[4-(methylsulfanyl)-1,3-benzothiazol-2-yl]oxy}phenyl)-3-(trifluoromethyl)pentan-3-ol.13. A pharmaceutical composition comprising a compound of claim 1, or apharmaceutically acceptable enantiomer, salt or solvate thereof, and atleast one pharmaceutically acceptable carrier, diluent, excipient and/oradjuvant.
 14. The pharmaceutical composition of claim 13 in the form ofan eyedrop.
 15. A method of treating an inflammatory disease orinflammatory condition comprising administrating to a subject in needthereof an effective amount of a compound of claim
 1. 16. The method ofclaim 15 for treating an ocular inflammatory disease or an ocularinflammatory condition.
 17. A method of treating a respiratory diseaseor condition comprising administering to a subject in need thereof atherapeutically-effective amount of a compound of claim
 1. 18. A methodof treating a neurodegenerative disease, condition or disordercomprising administering to a subject in need thereof atherapeutically-effective amount of a compound of claim
 1. 19. Acompound of formula (1)

or a pharmaceutically acceptable enantiomer, diastereomer, salt, orsolvate thereof, wherein: Ar is a 9- or 10-membered bicyclic aromaticring system, where Ar is optionally substituted with one, two or threesubstituents; L is selected from a direct bond and methylene; R¹ isselected from hydrogen, halide, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy,C₃-C₆cycloalkoxy and C₁-C₆alkoxy substituted with C₃-C₆cycloalkyl; A isselected from a direct bond, —CH₂— and —CH₂CH₂—; E is selected from—C(O)—R², C(OR³)R⁴R⁵ and CH(R⁶)NR⁷R⁸; R² is selected from methyl, ethyland phenyl; R³ is selected from H, alkyl and substituted alkyl; R⁴ isselected from hydrogen, alkyl and phenyl; R⁵ is selected fromC₁-C₇alkyl, C₁-C₇haloalkyl, phenyl and substituted phenyl; R⁶ isselected from hydrogen, methyl, halogenated methyl and ethyl; R⁷ ishydrogen; and R⁸ is hydrogen, methyl or ethyl; with the proviso thattogether, R⁷ and R⁸ may form a 5 or 6-membered, optionally substituted,heterocycle.
 20. A pharmaceutical composition comprising a compoundaccording to claim 19, or a pharmaceutically acceptable enantiomer, saltor solvate thereof, and at least one pharmaceutically acceptablecarrier, diluent, excipient and/or adjuvant. 21.-102. (canceled)